EP1363885B1 - Substituted propane-1,3-diamine derivatives and the pharmaceutical use thereof - Google Patents

Substituted propane-1,3-diamine derivatives and the pharmaceutical use thereof Download PDF

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Publication number
EP1363885B1
EP1363885B1 EP02714169A EP02714169A EP1363885B1 EP 1363885 B1 EP1363885 B1 EP 1363885B1 EP 02714169 A EP02714169 A EP 02714169A EP 02714169 A EP02714169 A EP 02714169A EP 1363885 B1 EP1363885 B1 EP 1363885B1
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syn
methyl
phenyl
dimethylamino
cyclohexyl
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German (de)
French (fr)
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EP1363885A1 (en
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Bernd Sundermann
Helmut Buschmann
Babette-Yvonne Kögel
Beatrix Merla
Nikolaus Risch
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Gruenenthal GmbH
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Gruenenthal GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to substituted propane-1,3-diamine derivatives, processes for their preparation, medicaments and pharmaceutical compositions containing them and their use for the preparation of medicaments for the treatment and / or prophylaxis of pain, urinary incontinence, itching, tinnitus aurium and / or diarrhea.
  • Classic opioids such as morphine are effective in the treatment of severe to severe pain. Their use, however, is limited by the known side effects, e.g. Respiratory depression, vomiting, sedation, constipation and tolerance development, limited. In addition, they are less effective in the case of neuropathic or incidental pain, in particular tumor patients.
  • these substances should as far as possible not cause any of the side effects usually associated with the use of opioids with ⁇ receptor affinity, such as morphine, such as nausea, vomiting, addiction, respiratory depression or constipation.
  • the compounds of general structure (I) may be present as a racemate, in the form of one or more of their diastereomers or one or more of their enantiomers.
  • Pharmaceutically acceptable salts within the meaning of this invention are those salts of the compounds according to the general structure (I) according to the invention which are physiologically compatible when used pharmaceutically - in particular when used on mammals and / or humans.
  • Such pharmaceutically acceptable salts can be formed, for example, with inorganic or organic acids.
  • the pharmaceutically-acceptable salts of the compounds of this invention are formed with hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic, acetic, oxalic, succinic, tartaric, mandelic, fumaric, lactic, citric, glutamic or aspartic acids.
  • the formed salts include hydrochlorides, hydrobromides, phosphates, carbonates, bicarbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutaminates.
  • solvates and in particular the hydrates of the compounds of the invention which can be obtained, for example, by crystallization from aqueous solution.
  • the compounds of general structure (I) according to the invention can thus be used as racemate, in the form of one or more of their diastereomers, i. diastereomerically pure or as a mixture of two or more diastereomers, or in the form of one or more of their enantiomers, i. enantiomerically pure or as a nonracemic mixture of enantiomers, both in substance and as pharmaceutically acceptable salts of these compounds.
  • the mixtures can be present in any mixing ratio of the stereoisomers.
  • the compounds of the invention of the general formula (I), or one of their pharmaceutically acceptable salts, as diastereomers of the formula (syn, anti-I) and optionally enantiomerically pure are preferred.
  • compounds of general structure (I) or their pharmaceutically acceptable salts which are diastereomers of the formula (anti, anti-I) and optionally enantiomerically pure.
  • compounds of general structure (I) or their pharmaceutically acceptable salts which are used as diastereomers of the formula (anti, syn-I) and optionally enantiomerically pure.
  • compounds of the general structure (I) or their pharmaceutically acceptable salts are preferred which are used as diastereomers of the formula (syn, syn-I) and optionally enantiomerically pure.
  • Another object of the present invention are methods for preparing the compounds of general structure (I).
  • compounds of the general structure (I) in which R 3 is H, n-propyl or -CH 2 -phenyl and R 4 is hydrogen can be obtained by reduction of the corresponding imine of the general formula (II) to be obtained.
  • the reduction is carried out at temperatures of - 70 ° C to +65 ° C, preferably 0 ° C to +40 ° C, over a period of 0.5 h to 24 h.
  • This imine reduction process generally provides the diamine (I) as a mixture of various conceivable stereoisomers (Mixture of diastereomers).
  • the reduction can also be carried out with hydrogen (at an H 2 partial pressure of 1 to 50 bar) in the presence of a suitable transition metal catalyst, for example Ni, Pd, Pt or PtO 2 , preferably in situ.
  • the diamine (1) with the relative configuration of anti, with high stereoselectivity, anti receive.
  • the reduction in methanol is preferably carried out with slow heating from 0 ° C. to room temperature over 8 to 24 hours, in particular 10 to 14 hours.
  • This reduction is preferably carried out with L-selectride or diisobutylaluminum hydride (DIBAH), in particular in THF and with heating from 0 ° C. to room temperature over 8 to 24 hours, in particular 10 to 14 hours.
  • DIBAH diisobutylaluminum hydride
  • the diastereomeric product mixture of the non-stereoselectively conducted imine reduction process may be subjected to, for example, fractional crystallization, also of its salts, or chromatographic separation.
  • the imines of the formula (II) used in the non-stereoselective imine reduction process according to the invention are selected from the corresponding Mannich bases of the general structure (III) wherein R 1 , R 2 , R 5 , R 6 and A are as defined for formula (I) and (II), by reaction with ammonia or an equivalent reagent (when R 3 in FIG Formula (II) H) or with a primary amine R 3 NH 2 (when R 3 in (II) is not H, but n-propyl or -CH 2 -phenyl) readily accessible.
  • reaction of (III) with ammonium acetate in anhydrous methanol at temperatures from 0 ° C to 80 ° C, preferably at 20 to 25 ° C and with a reaction time of 0.5 h to 12 h, preferably from 30 min to 120 min, in particular 60 min, are carried out, especially if the subsequent reduction is carried out in methanol.
  • anti-configured imines are derived from the corresponding anti-configured Mannich bases (anti-III) accessible by reacting these with the primary amine R 3 NH 2 or with ammonia or an equivalent reagent, such as ammonium acetate, under the conditions given for the formation of (II) above.
  • Mannich bases (III) The preparation of the Mannich bases (III) is known per se from the literature and is described, for example, in the patent applications EP 1 043 307 A2 and EP 1 043 306 A2, which are incorporated herein by reference are hereby incorporated in detail in the disclosure of the present invention.
  • the 1,4-addition of secondary amines HNR 5 R 6 to enones of the general structure (XI) - which in turn are obtained by aldol condensation of ketones of the formula (IX) with aldehydes of the general formula (X) - leads to the desired Mannich Bases (II) (US Patent 4,017,637), which are generally obtained as a mixture of stereoisomers.
  • the Mannich bases (III) so obtained may be used as a mixture of the stereoisomers or may be prepared using techniques well known in the art, e.g. Crystallization or chromatography, separated into their diastereoisomers and reacted as such.
  • Mannich bases of preferably anti-diastereoselective configuration can be prepared by reacting enamines of general structure (XII) wherein the radicals R are, for example, alkyl or together form - (CH 2 ) 4 - or - (CH 2 ) 5 - with iminium salts of the general structure (VIII) in which Z ⁇ is a suitable counterion such as Cl ⁇ , Br ⁇ , I ⁇ or AlCl 4 ⁇ , prepared (EP 1 043 307 A2 and EP 1 043 306 A2).
  • the enamines are prepared by methods known in the literature from ketones of the general structure (IX) and secondary amines, e.g. Dimethylamine, pyrrolidine, piperidine or morpholine (Acta Chem. Scand. B 38 (1984) 49-53).
  • the iminium salts (VIII) are prepared by literature methods, e.g. by reacting amines of general structure (XIII) with acid chlorides, e.g.
  • syn-configured isomers can also be obtained from the anti-configured Mannich bases (anti-III) by reacting the Mannich base (anti-III) in a suitable solvent, eg an alcohol such as methanol or ethanol, or water, dissolved with a sufficiently strong acid, for example aqueous hydrochloric acid, dilute sulfuric acid or conc. Acetic acid, and stirred for about 8 to 24 hours; It is essential for the desired epimerization that the dissolved Mannich base (III) does not precipitate or crystallize out of the solution, but remains in solution.
  • a suitable solvent eg an alcohol such as methanol or ethanol, or water
  • a sufficiently strong acid for example aqueous hydrochloric acid, dilute sulfuric acid or conc.
  • Acetic acid and stirred for about 8 to 24 hours; It is essential for the desired epimerization that the dissolved Mannich base (III) does not precipitate or crystallize out of the solution, but remains in solution.
  • anti-Mannich base anti-III
  • syn-Mannich base syn-Mannich base
  • Another inventive method for preparing the compounds of general structure (I) according to the invention is based on an aminoalcohol of the general structure (IV), in a process step (a) in the corresponding mesylate or tosylate of the formula (V) wherein L mesyl (CH 3 SO 2 -) or tosyl (4-CH 3 -phenyl-SO 2 -), for example by reaction of (IV) with mesyl chloride (CH 3 SO 2 Cl) or tosyl chloride (p-toluenesulfonyl chloride, 4-CH 3 -phenyl) SO 2 Cl) in the presence of a base (eg triethylamine) is transferred; Subsequently, the mesilate or tosylate (V) is reacted in a process step (b), for example with sodium azide to the azide (VI), which is converted in a process step (c) with reduction in the novel diamine of the formula (I).
  • a base eg trieth
  • This method can also be applied so that a compound of the formula (I) according to the invention is preferably obtained in a certain relative configuration.
  • process step (a ') preferably proceeds to give the relative stereochemistry to the compound (anti, anti-V), while the subsequent azide formation (b ') proceeds by inversion of the configuration of the stereocenter at the OL carbon atom, thus giving the azide (syn, anti-V1).
  • Subsequent reduction of (syn, anti-VI) yields the diamine (syn, anti-I).
  • the diamine (anti, anti-I) is stereoselectively accessible when starting the process of the invention with an amino alcohol of the general structure (syn.anti-IV) and on the mesylate or tosylate of the general structure (syn, anti-V ) leads to the azide of the general structure (anti, anti-VI), which is finally reduced to the diamine (anti, anti-1).
  • the aminoalcohols of the formula (IV) used in this process are, according to EP 0 143 306 A2, starting from the corresponding Mannich bases (III) by reduction with a reducing agent such as, for example, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutylaluminum hydride or a complex analog of these compounds, at -70 to +110 ° C in suitable solvents, for example diethyl ether, THF, methanol or ethanol, available. If one starts, for example, from a Mannich base with anti-configuration (anti-III), the corresponding (anti, anti-IV) amino alcohol is obtained on reduction with NaBH 4 in ethanol at room temperature and a reaction time of 8 to 16 h.
  • a reducing agent such as, for example, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutylaluminum hydride or a complex analog of these compounds, at -70 to +110
  • the aminoalcohol (IV) can also be converted into the corresponding diamine (1) by Mitsunobu reaction by reaction first with dimethyl or diethyl azodicarboxylate, triphenylphosphane and a phthalimide and then with hydrazine Mitsunobu, Synthesis (1981) 1-28). Since this reaction proceeds by inversion of the stereochemistry at the O-carbon atom, the diamine (syn, anti-I) can be stereoselected from the alcohol (anti, anti-IV), while the diamine can be stereoselected from (syn, anti-IV) (anti, anti-I) can be obtained.
  • Suitable complex hydrides are e.g. Sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutyraluminum hydride, or a complex analogue of these compounds which may be used at -70 to +110 ° C in suitable solvents, e.g. Diethyl ether, THF, methanol or ethanol, optionally in admixture with methylene chloride, can be used.
  • suitable solvents e.g. Diethyl ether, THF, methanol or ethanol
  • imine (VII) is used in this (imine + iminium salt) process, for which R 3 is - (CH 2 ) -phenyl
  • This process step (cc) is preferably carried out with 10% palladium on carbon as transition metal, preferably in methanol.
  • the syn, anti-diastereomer of the compound (I) is preferably formed.
  • the starting compounds, reagents and solvents used in the processes used to prepare the diamines of the general structure (I) according to the invention are commercially available (from Acros, Geel, Avocado, Port of Heysham, Aldrich, Deisenhofen), unless otherwise specified in the description Fluka, Seelze, Lancaster, Mülheim, Maybridge, Tintagel, Merck, Darmstadt, Sigma, Deisenhofen, TCI, Japan) or may be prepared by methods well known in the art.
  • the compounds of the general structure (I) according to the invention can be isolated both in substance and as a salt.
  • the compound of the general structure (I) according to the invention is usually obtained after the reaction according to the above-described inventive method and subsequent conventional work-up.
  • the compound of general structure (I) thus obtained or obtained in situ without isolation can then be, for example, by reaction with an inorganic or organic acid, preferably hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic and acetic acid .
  • Citric acid, glutamic acid or aspartic acid are converted into the corresponding salt.
  • the salts formed include hydrochlorides, hydrobromides, phosphates, carbonates, bicarbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutaminates.
  • the most preferred hydrochloride formation may also be accomplished by the reaction of the base dissolved in a suitable organic solvent such as butan-2-one (methyl ethyl ketone) with trimethylsilyl chloride (TMSCl), advantageously in the presence of water.
  • TMSCl trimethylsilyl chloride
  • Another object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of general structure (I) as defined above, or one of its pharmaceutical salts, in particular the hydrochloride salt.
  • the pharmaceutical composition according to the invention contains in a pharmaceutical composition at least one of the above exemplified compounds in substance or as a pharmaceutically acceptable salt and optionally other active ingredients and excipients. It can do that Inventive diamine (I) as a racemate, in the form of one or more diastereomers or one or more enantiomers.
  • the medicaments containing them according to the invention are preferably in the prophylaxis and / or treatment of pain conditions, such.
  • pain conditions such as acute pain, chronic pain or neuropathic pain, especially strong to severe pain used.
  • the medicaments according to the invention can be used for the treatment and / or prophylaxis of diarrhea, urinary incontinence, itching and / or tinnitus aurium.
  • Another object of the present invention relates to the use of a diamine of the formula (I) or one of its pharmaceutically acceptable salts for the manufacture of a medicament for the prophylaxis and / or treatment of pain, diarrhea, urinary incontinence, itching and / or tinnitus aurium.
  • the medicaments, medicaments and pharmaceutical compositions according to the invention can be in the form of liquid, semisolid or solid dosage forms and in the form of, for example, injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, pellets, transdermal therapeutic systems, capsules, patches, suppositories, ointments , Creams, lotions, gels, emulsions or aerosols are present and administered and in addition to at least one compound of general structure (I) depending on galenic form and depending on the route of application pharmaceutical excipients, such as support materials, fillers, solvents, diluents, surface-active Fabrics, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and / or binders.
  • injection solutions for example, injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, pellets, transdermal therapeutic systems, capsules, patches, suppositories,
  • adjuvants may be, for example: Water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, Cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic gums, acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, kosnut nut oil, peanut oil, soybean oil, lecithin , Sodium lactate, polyoxyethylene and
  • excipients and the amounts to be used depend on whether the medicinal product / drug is administered orally, subcutaneously, parenterally, intravenously, vaginally, pulmonarily, intraperitoneally, transdermally, intramuscularly, nasally, buccally, rectally or locally, for example at infections on the skin Skin, the mucous membranes and the eyes, should be applied.
  • oral administration are, inter alia, preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups, for parenteral, topical and inhalative administration solutions, suspensions, easily reconstitutable powder for inhalation and sprays.
  • Compounds of the general structure (I) according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents, are suitable percutaneous administration preparations. Rectal, transmucosal, parenteral, oral or Percutaneously applicable preparation forms can release the compounds of the general structure (I) according to the invention with a delay.
  • compositions of the present invention are accomplished by means well known in the art of pharmaceutical formulation, devices, methods and methods, as described, for example, in "Remington's Pharmaceutical Sciences", ed. A.R. Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa. (1985), especially in Part 8, Chapters 76 to 93.
  • the active ingredient of the drug ie a compound of general structure (I) or one of its pharmaceutically acceptable salts
  • a pharmaceutical carrier eg conventional tablet ingredients, such as corn starch, lactose, sucrose, sorbitol , Talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, such as water, to form a solid composition containing a compound of the invention or a pharmaceutically acceptable salt thereof in homogeneous distribution.
  • the active ingredient is distributed evenly throughout the composition so that it can be readily subdivided into equally effective unit dose forms such as tablets, pills or capsules.
  • the solid composition is then subdivided into unit dose forms.
  • the tablets or pills of the drug or compositions of the invention may also be coated or otherwise compounded to provide a sustained release dosage form.
  • Suitable coating agents include polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and / or cellulose acetate.
  • the amount of drug to be administered to the patient varies and depends on the weight, age and history of the patient, as well as the route of administration, the indication and the severity of the disease. Usually, 0.005 to 500 mg / kg, in particular 0.05 to 5 mg / kg, preferably 2 to 250 mg / kg body weight of at least one compound of the general structure (I) according to the invention are applied.
  • the chemicals and solvents used were from Acros, Geel; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka, Seelze; Lancaster, Mülheim; Maybridge, Tintagel; Merck, Darmstadt; Sigma, Deisenhofen or TCI, Japan purchased by purchase or synthesized by conventional and known in the art.
  • ESI mass spectra were recorded on a LCQ Classic mass spectrometer from Finnigan, the 1 H and 13 C NMR spectra were recorded on a 300 (75) MHz Avance DPX 300 NMR instrument, a 600- ( 150-) MHz Avance DRX-600 NMR instrument or a Bruker ARX 200 NMR instrument from Bruker, using tetramethylsilane as the internal standard.
  • IR spectra were recorded on a Nicolet 510P FT-IR spectrometer.
  • GC / MS data was obtained on a Finnigan MAT Magnum System 240 instrument. Elemental analyzes were carried out with a Perkin Elmer Elemental Analyzer and provided adequate elemental analysis results: C ⁇ 0.34, H ⁇ 0.28, N ⁇ 0.19.
  • the reaction vessel was baked in a drying oven.
  • the organic phase was dried over magnesium sulfate and concentrated at 40 ° C in vacuo.
  • the crude product obtained was purified by MPLC (eluent n-hexane, gradual addition of diethyl ether up to 100%).
  • the final hydrochloride precipitation was carried out by dissolving the crude base in about 10 ml of 2-butanone per gram of base, then adding half a molar equivalent of water followed by 1.1 molar equivalents of chlorotrimethylsilane and stirring overnight. The precipitated hydrochloride was filtered off and dried in vacuo.
  • the compounds prepared by way of example according to AAV 1-6 are shown in Table 1.
  • the determination of the stereochemistry was carried out by means of 1 H and 13 C NMR investigations, in particular by comparison of the chemical shifts of the C atoms C-NR 3 R 4 , CR 1 and CA in the 13 C-NMR spectrum of the compounds according to the invention with one another and with the displacements of the corresponding C atoms in the 13 C-NMR spectrum of (anti, anti) -1-hydroxy-2- (pyrrolidine-phenyl-methyl) -cyclohexane and (syn, anti) -1-hydroxy-2- (pyrrolidin-phenyl-methyl) -cyclohexane.
  • Table 1 ⁇ / u> Example no.
  • connection Manufacturing process (AAV) 1 (Syn, syn) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] benzamide hydrochloride 4A / B + 5 + 6 1a (Syn, syn) -2- (dimethylamino-3-ylmethyl) cyclohexylamine 4A / B 2 (Syn, syn) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] -2-fluorobenzamide hydrochloride 4A / B + 5 + 6 3 (Syn, syn) -2-chloro-N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] benzamide hydrochloride 4A / B + 5 + 6 4 (Syn, syn) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] benzamide hydrochloride 4A /
  • the assay for analgesic activity was carried out in phenyl-quinone-induced writhing in the mouse (modified according to IC Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240).
  • male NMRI mice weighing 25 to 30 g were used.
  • groups of 10 animals per substance dose received 0.3 ml / mouse of a 0.02% strength aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen, preparation of the solution with the addition of 5% ethanol and storage in a water bath at 45 ° C) intraperitoneally.
  • the animals were placed individually in observation cages.

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Abstract

The invention relates to substituted propane-1,3-diamine derivatives of general formula (I), to methods for producing said derivatives, to medicaments and pharmaceutical compositions containing the same, and to the use thereof for producing pharmaceuticals for the treatment and/or prophylaxis of pain, urinary incontinence, itching, tinnitus aurium and/or diarrhoea.

Description

Die vorliegende Erfindung betrifft substituierte Propan-1,3-diamin-Derivate, Verfahren zu ihrer Herstellung, sie enthaltende Arzneimittel und pharmazeutische Zusammensetzungen sowie ihre Verwendung zur Herstellung von Arzneimitteln zur Behandlung und/oder Prophylaxe von Schmerz, Harninkontinenz, Juckreiz, Tinnitus aurium und/oder Diarrhoe.The present invention relates to substituted propane-1,3-diamine derivatives, processes for their preparation, medicaments and pharmaceutical compositions containing them and their use for the preparation of medicaments for the treatment and / or prophylaxis of pain, urinary incontinence, itching, tinnitus aurium and / or diarrhea.

Die Behandlung chronischer und nicht chronischer Schmerzzustände hat in der Medizin eine große Bedeutung. Es besteht ein weltweiter Bedarf an gut wirksamen Therapien für eine patientengerechte und zielorientierte Behandlung chronischer und nicht chronischer Schmerzzustände, wobei hierunter die erfolgreiche und zufriedenstellende Schmerzbehandlung für den Patienten zu verstehen ist.The treatment of chronic and non-chronic pain is of great importance in medicine. There is a worldwide need for effective therapies for a patient-oriented and goal-oriented treatment of chronic and non-chronic pain states, which is to be understood as successful and satisfactory pain treatment for the patient.

Klassische Opioide wie Morphin sind bei der Therapie starker bis stärkster Schmerzen gut wirksam. Ihr Einsatz wird jedoch durch die bekannten Nebenwirkungen, wie z.B. Atemdepression, Erbrechen, Sedierung, Obstipation und Toleranzentwicklung, limitiert. Außerdem sind sie bei neuropathischen oder inzidentiellen Schmerzen, unter denen insbesondere Tumorpatienten leiden, weniger wirksam.Classic opioids such as morphine are effective in the treatment of severe to severe pain. Their use, however, is limited by the known side effects, e.g. Respiratory depression, vomiting, sedation, constipation and tolerance development, limited. In addition, they are less effective in the case of neuropathic or incidental pain, in particular tumor patients.

Der vorliegenden Erfindung liegt als Aufgabe zugrunde, analgetisch wirksame Verbindungen zur Verfügung zu stellen, die sich zur Schmerztherapie - insbesondere auch zur Therapie chronischer und neuropathischer Schmerzen - eignen. Darüber hinaus sollten diese Substanzen möglichst keine der Nebenwirkungen, die üblicherweise bei der Anwendung von Opioiden mit µ-Rezeptoraffinität wie Morphin auftreten, wie z.B. Übelkeit, Erbrechen, Abhängigkeit, Atemdepression oder Obstipation, hervorrufen.It is an object of the present invention to provide analgesically active compounds which are suitable for the treatment of pain - in particular also for the treatment of chronic and neuropathic pain. In addition, these substances should as far as possible not cause any of the side effects usually associated with the use of opioids with μ receptor affinity, such as morphine, such as nausea, vomiting, addiction, respiratory depression or constipation.

Diese Aufgabe wird durch die Verbindungen der allgemeinen Struktur (l) gelöst, die analgetisch wirksam sind. Bei den erfindungsgemäßen Verbindungen handelt es sich um substituierte 1,3-Propan-diamin-Derivate der allgemeinen Struktur (l) sowie ihre pharmazeutisch akzeptablen Salze

Figure imgb0001
worin

R1
Methyl oder Ethyl bedeutet,
R2
Methyl, Ethyl oder Phenyl bedeutet,
oder
R1 und R2
zusammen -(CH2)4- bilden;
R3
H, n-Propyl, -CH2-Phenyl oder C(=O)-R7 bedeutet;
R4
H bedeutet;
R5 und R6
jeweils Methyl bedeuten oder zusammen -(CH2)2-O-(CH2)2- bilden;
A
Phenyl, 2-Chlorphenyl, 2-Methoxyphenyl, 2-Nitrophenyl oder Pyridin-3-yl bedeutet; und
R7
Methyl, Phenyl, 2-Fluorphenyl, 2-Chlorphenyl oder 2-Methylphenyl bedeutet.
This object is achieved by the compounds of general structure (I) which are analgesically effective. The compounds according to the invention are substituted 1,3-propanediamine derivatives of the general structure (I) and their pharmaceutically acceptable salts
Figure imgb0001
 wherein
R 1
Methyl or ethyl means
R 2
Methyl, ethyl or phenyl,
or
R 1 and R 2
together form - (CH 2 ) 4 -;
R 3
H, n-propyl, -CH 2 -phenyl or C (= O) -R 7 ;
R 4
H means;
R 5 and R 6
each methyl or together - (CH 2 ) 2 -O- (CH 2 ) 2 - form;
A
Phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-nitrophenyl or pyridin-3-yl; and
R 7
Methyl, phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-methylphenyl.

Die Verbindungen der allgemeinen Struktur (I) können als Racemat, in Form eines oder mehrerer ihrer Diastereomeren oder eines oder mehrerer ihrer Enantiomeren vorliegen.The compounds of general structure (I) may be present as a racemate, in the form of one or more of their diastereomers or one or more of their enantiomers.

Folgende Verbindungen der allgemeinen Struktur (1) sind im Stand der Technik bereits bekannt (Synlett (1997), 177-178), ohne daß deren Verwendung in einem Arzneimittel oder zur Herstellung eines Arzneimittels zur Therapie und/oder Prophylaxe von Schmerz, Harninkontinenz, Juckreiz, Tinnitus aurium und/oder Diarrhoe beschrieben wird: N,N-Dimethyl-[phenyl-(2-pyrrolidin-1-yl-cyclohexyl)-methyl]-amin, N,N-Dimethyl-[(2-morpholin-4-yl-cyclohexyl)-phenyl-methyl]-amin, 4-[Phenyl-(2-pyrrolidin-1-yl-cyclohexyl)-methyl]-pyrrolidin, 4-[Phenyl-(2-pyrrolidin-1-yl-cyclohexyl)-methyl]-morpholin, 1-[Phenyl-(2-pyrrolidin-1-yi-cyclohexyl)-methyl]-piperidin, 1-[2-Methyl-1-(2-pyrrolidin-1-yl-cyclohexyl)-propyl]-piperidin, N,N-Dimethyl-(2-methyl-1,3-diphenyl-3-pyrrolid in-1-yl-propyl)-amin, N,N-Dimethyl-(2-methyl-1,3-diphenyl-3-(N,N-diethylamino)-propyl)-amin, 4-(1,3-Diphenyl-3-pyrrolidin-1-yl-propyl)-morpholin, N,N-Dimethyl-(2-methyl-1-phenyl-3-(morpholin-4-yl)-pentyl)-amin, Benzyl-[2-(dimethylamino-phenyl-methyl) cyclohexyl]-amin, (2-Methyl-1,3-diphenyl-3-piperidin-1-yl-propyl)-propylamin. Diese Verbindungen sind daher insoweit ebenfalls Gegenstand der vorliegenden Erfindung, als erfindungsgemäße Verfahren zu ihrer Herstellung, sie enthaltende Arzneimittel sowie ihre Verwendung zur Herstellung von Medikamenten zur Behandlung und/oder Prophylaxe von Schmerz, Harninkontinenz, Juckreiz, Tinnitus aurium und/oder Diarrhoe betroffen sind.The following compounds of general structure (1) are already known in the art (Synlett (1997), 177-178), without their use in a pharmaceutical or for the manufacture of a medicament for the therapy and / or prophylaxis of pain, urinary incontinence, itching , Tinnitus aurium and / or diarrhea: N, N-dimethyl- [phenyl- (2-pyrrolidin-1-yl-cyclohexyl) -methyl] -amine, N, N-dimethyl - [(2-morpholin-4-yl-cyclohexyl) -phenyl-methyl] -amine, 4- [phenyl- (2-pyrrolidin-1-yl-cyclohexyl) -methyl] -pyrrolidine, 4- [Phenyl- (2-pyrrolidin-1-ylcyclohexyl) methyl] morpholine, 1- [phenyl (2-pyrrolidin-1-yl-cyclohexyl) methyl] -piperidine, 1- [2-methyl-1 - (2-pyrrolidin-1-yl-cyclohexyl) -propyl] -piperidine, N, N-dimethyl- (2-methyl-1,3-diphenyl-3-pyrrolidinyl-1-yl-propyl) -amine, N , N-dimethyl- (2-methyl-1,3-diphenyl-3- (N, N-diethylamino) -propyl) -amine, 4- (1,3-diphenyl-3-pyrrolidin-1-yl-propyl) -morpholine, N, N-dimethyl- (2-methyl-1-phenyl-3- (morpholin-4-yl) -pentyl) -amine, benzyl- [2- (dimethylamino-phenyl-methyl) cyclohexyl] -amine, (2-methyl-1,3-diphenyl-3-piperidin-1-yl-propyl) propylamine. These compounds are therefore also the subject of the present invention, as inventive method for their preparation, they containing drugs and their use for the preparation of medicaments for the treatment and / or prophylaxis of pain, urinary incontinence, itching, tinnitus aurium and / or diarrhea are concerned.

Pharmazeutisch annehmbare (akzeptable) Salze im Sinne dieser Erfindung sind solche Salze der erfindungsgemäßen Verbindungen gemäß der allgemeinen Struktur (I), die bei pharmazeutischer Verwendung physiologisch - insbesondere bei Anwendung am Säugetier und/oder Menschen - verträglich sind. Solche pharmazeutisch annehmbaren Salze können beispielsweise mit anorganischen oder organischen Säuren gebildet werden.Pharmaceutically acceptable salts within the meaning of this invention are those salts of the compounds according to the general structure (I) according to the invention which are physiologically compatible when used pharmaceutically - in particular when used on mammals and / or humans. Such pharmaceutically acceptable salts can be formed, for example, with inorganic or organic acids.

Vorzugsweise werden die pharmazeutisch annehmbaren Salze der erfindungsgemäßen Verbindungen mit Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, p-Toluolsulfonsäure, Kohlensäure, Ameisensäure, Essigsäure, Oxalsäure, Bernsteinsäure, Weinsäure, Mandelsäure, Fumarsäure, Milchsäure, Citronensäure, Glutaminsäure oder Asparaginsäure gebildet. Bei den gebildeten Salzen handelt es sich u. a. um Hydrochloride, Hydrobromide, Phosphate, Carbonate, Hydrogencarbonate, Formiate, Acetate, Oxalate, Succinate, Tartrate, Fumarate, Citrate und Glutaminate. Ebenfalls bevorzugt sind Solvate und insbesondere die Hydrate der erfindungsgemäßen Verbindungen, die z.B. durch Kristallisation aus wäßriger Lösung erhalten werden können.Preferably, the pharmaceutically-acceptable salts of the compounds of this invention are formed with hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic, acetic, oxalic, succinic, tartaric, mandelic, fumaric, lactic, citric, glutamic or aspartic acids. With the formed salts These include hydrochlorides, hydrobromides, phosphates, carbonates, bicarbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutaminates. Also preferred are solvates and in particular the hydrates of the compounds of the invention, which can be obtained, for example, by crystallization from aqueous solution.

Die erfindungsgemäßen Verbindungen der allgemeinen Struktur (I) weisen stets mindestens drei Asymmetriezentren auf, die in der untenstehenden Formel mit * gekennzeichnet sind:

Figure imgb0002
The compounds of the general structure (I) according to the invention always have at least three asymmetric centers which are marked * in the formula below:
Figure imgb0002

Die erfindungsgemäßen Verbindungen der allgemeinen Struktur (I) können somit als Racemat, in Form eines oder mehrerer ihrer Diastereomeren, d.h. diastereomerenrein oder als Mischung zweier oder mehrerer Diastereomeren, oder in Form eines oder mehrerer ihrer Enantiomeren vorliegen, d.h. enantiomerenrein oder als nichtracemische Mischung von Enantiomeren, und zwar sowohl in Substanz als auch als pharmazeutisch annehmbare Salze dieser Verbindungen. Die Mischungen können in jedem beliebigen Mischungsverhältnis der Stereoisomeren vorliegen.The compounds of general structure (I) according to the invention can thus be used as racemate, in the form of one or more of their diastereomers, i. diastereomerically pure or as a mixture of two or more diastereomers, or in the form of one or more of their enantiomers, i. enantiomerically pure or as a nonracemic mixture of enantiomers, both in substance and as pharmaceutically acceptable salts of these compounds. The mixtures can be present in any mixing ratio of the stereoisomers.

Dabei ist es bevorzugt, daß die erfindungsgemäßen Verbindungen der allgemeinen Formel (I), oder eines ihrer pharmazeutisch annehmbaren Salze, als Diastereomeren der Formel (syn,anti-I)

Figure imgb0003
und gegebenenfalls enantiomerenrein vorliegen. Die für die Kennzeichnung der relativen Konfiguration (relativen Stereochemie) gewählte Bezeichnung "syn,anti" ist so zu verstehen, daß die beiden benachbarten Substituenten NR3R4 und R1 in der oben gezeigten Konformation in die gleiche Raumhälfte weisen (= "syn"), während die beiden benachbarten Substituenten R1 und NR5R6 in der gezeigten Konformation in entgegengesetzte Raumhälften (= "anti") weisen (S. Masamune et al., J. Am. Chem. Soc. (1982) 104, 5521-5523).It is preferred that the compounds of the invention of the general formula (I), or one of their pharmaceutically acceptable salts, as diastereomers of the formula (syn, anti-I)
Figure imgb0003
 and optionally enantiomerically pure. The term "syn, anti" chosen for the designation of the relative configuration (relative stereochemistry) is to be understood so that the two adjacent substituents NR 3 R 4 and R 1 in the conformation shown above have the same half-space (= "syn" ), while the two adjacent substituents R 1 and NR 5 have R 6 in the conformation shown in opposite halves of the space (= "anti") (S.Masamune et al., J. Am. Chem. Soc. (1982) 104, 5521 -5523).

Ebenfalls bevorzugt sind Verbindungen der allgemeinen Struktur (I) bzw. ihre pharmazeutisch annehmbaren Salze, die als Diastereomeren der Formel (anti,anti-I)

Figure imgb0004
und gegebenenfalls enantiomerenrein vorliegen. Die für die Kennzeichnung der relativen Stereochemie gewählte Bezeichnung "anti,anti" ist so zu verstehen, daß die beiden benachbarten Substituenten NR3R4 und R1 in der gezeigten Konformation ebenso in entgegengesetzte Raumhälften weisen (= "anti"), wie die beiden benachbarten Substituenten R1 und NR5R6.Also preferred are compounds of general structure (I) or their pharmaceutically acceptable salts, which are diastereomers of the formula (anti, anti-I)
Figure imgb0004
 and optionally enantiomerically pure. The term "anti, anti" chosen for the designation of the relative stereochemistry is to be understood so that the two adjacent substituents NR 3 R 4 and R 1 in the conformation shown likewise point into opposite halves of the space (= "anti"), like the two adjacent substituents R 1 and NR 5 R 6 .

Außerdem bevorzugt sind Verbindungen der allgemeinen Struktur (I) bzw. ihre pharmazeutisch annehmbaren Salze, die als Diastereomeren der Formel (anti,syn-I)

Figure imgb0005
und gegebenenfalls enantiomerenrein vorliegen. Die für die Kennzeichnung der relativen Stereochemie gewählte Bezeichnung "anti,syn" ist so zu verstehen, daß die beiden benachbarten Substituenten NR3R4 und R1 in der gezeigten Konformation in entgegengesetzte Raumhälften weisen (= "anti"), während die beiden benachbarten Substituenten R1 und NR5R6 in der gezeigten Konformation in die gleiche Raumhälfte (= "syn") weisen.Also preferred are compounds of general structure (I) or their pharmaceutically acceptable salts, which are used as diastereomers of the formula (anti, syn-I)
Figure imgb0005
 and optionally enantiomerically pure. The term "anti, syn" chosen for the designation of relative stereochemistry is to be understood so that the two adjacent substituents NR 3 R 4 and R 1 in the conformation shown point into opposite halves of the space (= "anti"), while the two adjacent ones Substituents R 1 and NR 5 R 6 in the conformation shown in the same space half (= "syn") have.

Ferner sind Verbindungen der allgemeinen Struktur (I) bzw. ihre pharmazeutisch annehmbaren Salze bevorzugt, die als Diastereomeren der Formel (syn,syn-I)

Figure imgb0006
und gegebenenfalls enantiomerenrein vorliegen. Die für die Kennzeichnung der relativen Stereochemie gewählte Bezeichnung "syn,syn " ist so zu verstehen, daß die beiden benachbarten Substituenten NR3R4 und R1 in der gezeigten Konformation ebenso in die gleiche Raumhälfte weisen (= "syn") wie die beiden benachbarten Substituenten R1 und NR5R6.Furthermore, compounds of the general structure (I) or their pharmaceutically acceptable salts are preferred which are used as diastereomers of the formula (syn, syn-I)
Figure imgb0006
 and optionally enantiomerically pure. The designation "syn, syn" chosen for the labeling of the relative stereochemistry is to be understood so that the two adjacent substituents NR 3 R 4 and R 1 in the conformation shown also point into the same half-space (= "syn") as the two adjacent substituents R 1 and NR 5 R 6 .

Beispielhafte und vorteilhafte Verbindungen der vorliegenden Erfindung sind aus der Gruppe ausgewählt, die

  • (syn,syn)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-benzamid oder sein Hydrochlorid
  • (syn,syn)2-(Dimethylaminopyridin-3-ylmethyl)cyclohexylamin oder sein Hydrochlorid
  • (syn,syn)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-fluorbenzamid oder sein Hydrochlorid
  • (syn,syn)-2-Chlor-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-benzamid oder sein Hydrochlorid
  • (anti,anti)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-benzamid oder sein Hydrochlorid
  • (anti,anti)-2-(Dimethylaminopyridin-3-ylmethyl)cyclohexylamin oder sein Hydrochlorid
  • (anti,anti)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-fluorbenzamid oder sein Hydrochlorid
  • (anti,anti)-2-Chlor-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]benzamid oder sein Hydrochlorid
  • (anti,anti)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-methylbenzamid oder sein Hydrochlorid
  • (syn,syn)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-methylbenzamid oder sein Hydrochlorid
  • (syn,syn)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]acetamid oder sein Hydrochlorid
  • (anti,anti)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]acetamid oder sein Hydrochlorid
  • (syn,syn)-N-[2-(Dimethylaminophenylmethyl)cyclohexyl]-2-fluorbenzamid oder sein Hydrochlorid
  • (syn,syn)-2-(Dimethylaminophenylmethyl)cyclohexylamin oder sein Hydrochlorid
  • (syn,syn)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-acetamid oder sein Hydrochlorid
  • (syn,syn)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-benzamid oder sein Hydrochlorid
  • (syn,syn)-2-Chlor-N-[2-(dimethylamino-phenyl-methyl)-cyclohexyl]-benzamid oder sein Hydrochlorid
  • (syn,syn)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-2-methyl-benzamid oder sein Hydrochlorid
  • (anti,anti)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-acetamid oder sein Hydrochlorid
  • (anti,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin oder sein Hydrochlorid
  • (anti,anti)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-benzamid oder sein Hydrochlorid
  • (anti,anti)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-2-methyl-benzamid oder sein Hydrochlorid
  • (syn,syn)-2-Chlor-N-{2-[(2-chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-benzamid oder sein Hydrochlorid
  • (syn,syn)-2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexylamin oder sein Hydrochlorid
  • (anti,anti)-2-Chlor-N-{2-[(2-chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-benzamid oder sein Hydrochlorid
  • (anti,anti)-2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexylamin oder sein Hydrochlorid
  • (syn,syn)-N-{2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-2-fluor-benzamid oder sein Hydrochlorid
  • (anti,anti)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-benzamide oder sein Hydrochlorid
  • (anti,anti)-2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexylamin oder sein Hydrochlorid
  • (anti,anti)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-2-fluor-benzamid oder sein Hydrochlorid
  • (ant,anti)-2-Chlor-N-{2-[dimethylamino-(2-nitro-phenyl)-methylcyclohexyl}-benzamid oder sein Hydrochlorid
  • (anti,anti)-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-2-methyl-benzamid oder sein Hydrochlorid
  • (syn,syn)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-acetamid oder sein Hydrochlorid
  • (syn,syn)-N-2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexylamin oder sein Hydrochlorid
  • (anti,anti)-N-{2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-acetamid oder sein Hydrochlorid
  • (syn,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin
  • (syn,anti)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-benzamid
  • (anti,anti)-N-{2-[Dimethylamino-(2-methoxy-phenyl)-methyl]-cyclohexyl}-benzamid
  • (anti,anti)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-benzamid
  • (anti,anti)-N-{2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-benzamid
  • (anti,anti)-N-{2-[Dimethylamino-(2-methoxy-phenyl)-methyl]-cyclohexyl}-acetamid
  • (anti,anti)-2-[Dimethylamino-(2-methoxy-phenyl)-methyl]-cyclohexylamin
  • (anti,anti)-N-{-2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-acetamid
  • (anti,anti)-2-[(2-chlor-phenyl)-dimethylamino-methyl]-cyclohexylamin
  • (anti,anti)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-acetamid
  • (anti,anti)-2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexylamin
  • (syn,syn)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin
  • (syn,syn)-2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexylamin
  • (anti,anti)-2-Chlor-N-(3-dimethylamino-1-ethyl-2-methyl-3-phenylpropyl)-benzamid
  • (anti,anti)-3-Dimethylamino-1-ethyl-2-methyl-3-phenyl-propylamin
  • (syn,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexyl-N-(n-propyl)-amin
  • (syn,anti)-2-(Morpholin-4-yl-phenyl-methyl)-cyclohexyl-N-(n-propyl)-amin
  • (syn,anti)-2,N,N-Trimethyl-1,3-diphenyl-N'-propyl-propan-1,3-diamin
  • (syn,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexyl-N-benzyl-amin
  • (syn,anti)-2-(Morpholin-4-yl-phenyl-methyl)-cyclohexyl-N-benzyl-amin
  • (syn,anti)-2,N,N-Trimethyl-1,3-diphenyl-N'-benzyl-propan-1,3-diamin
  • (syn,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin
  • (syn,anti)-2-(Morpholin-4-yl-phenyl-methyl)-cyclohexylamin
  • (syn,anti)-2,N,N-Trimethyl-1,3-diphenyl-propan-1,3-diamin
  • (syn,anti)-2-[(2-Chlorphenyl)-dimethylamino-methyl]-cyclohexylamin
  • (anti,anti)-2-[(2-Chlorphenyl)-dimethylamino-methyl]-cyclohexylamin
  • (syn,syn)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin
  • (anti,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin
  • (syn,syn)-2-[(2-Chlorphenyl)-dimethylamino-methyl]-cyclohexylamin
  • (syn,syn)-2-(Dimethylamino-pyridin-3-yl-methyl)-cyclohexylamin
  • (anti,anti)-2-(Dimethylamino-pyridin-3-yl-methyl)cyclohexylamin
  • (syn,syn)-2-(Dimethylamino-(2-methoxyphenyl)-methyl)-cyclohexylamin
  • (anti,anti)-2-(Dimethylamino-(2-methoxyphenyl)-methyl)-cyclohexylamin
  • (syn,syn)-2-(Dimethylamino-(2-nitrophenyl)-methyl)-cyclohexylamin
  • (anti,anti)-2-(Dimethylamino-(2-nitrophenyl)-methyl)-cyclohexylamin
umfaßt.Exemplary and advantageous compounds of the present invention are selected from the group consisting of
  • (syn, syn) -N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] benzamide or its hydrochloride
  • (syn, syn) 2- (dimethylaminopyridin-3-ylmethyl) cyclohexylamine or its hydrochloride
  • (syn, syn) -N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] -2-fluorobenzamide or its hydrochloride
  • (syn, syn) -2-chloro-N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] benzamide or its hydrochloride
  • (anti, anti) -N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] benzamide or its hydrochloride
  • (anti, anti) -2- (dimethylaminopyridin-3-ylmethyl) cyclohexylamine or its hydrochloride
  • (anti, anti) -N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] -2-fluorobenzamide or its hydrochloride
  • (anti, anti) -2-chloro-N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] benzamide or its hydrochloride
  • (anti, anti) -N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] -2-methylbenzamide or its hydrochloride
  • (syn, syn) -N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] -2-methylbenzamide or its hydrochloride
  • (syn, syn) -N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] acetamide or its hydrochloride
  • (anti, anti) -N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] acetamide or its hydrochloride
  • (syn, syn) -N- [2- (dimethylaminophenylmethyl) cyclohexyl] -2-fluorobenzamide or its hydrochloride
  • (syn, syn) -2- (dimethylaminophenylmethyl) cyclohexylamine or its hydrochloride
  • (syn, syn) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -acetamide or its hydrochloride
  • (syn, syn) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -benzamide or its hydrochloride
  • (syn, syn) -2-chloro-N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -benzamide or its hydrochloride
  • (syn, syn) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -2-methyl-benzamide or its hydrochloride
  • (anti, anti) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -acetamide or its hydrochloride
  • (anti, anti) -2- (dimethylamino-phenyl-methyl) -cyclohexylamine or its hydrochloride
  • (anti, anti) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -benzamide or its hydrochloride
  • (anti, anti) -N- [2- (dimethylamino-phenylmethyl) -cyclohexyl] -2-methylbenzamide or its hydrochloride
  • (syn, syn) -2-chloro-N- {2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexyl} -benzamide or its hydrochloride
  • (syn, syn) -2 - [(2-chloro-phenyl) -dimethyl-amino-methyl] -cyclohexylamine or its hydrochloride
  • (anti, anti) -2-chloro-N- {2 - [(2-chloro-phenyl) -dimethyl-amino-methyl] -cyclohexyl} -benzamide or its hydrochloride
  • (anti, anti) -2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexylamine or its hydrochloride
  • (syn, syn) -N- {2 - [(2-chloro-phenyl) -dimethyl-amino-methyl] -cyclohexyl} -2-fluoro-benzamide or its hydrochloride
  • (anti, anti) -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -benzamide or its hydrochloride
  • (anti, anti) -2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexylamine or its hydrochloride
  • (anti, anti) -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -2-fluoro-benzamide or its hydrochloride
  • (ant, anti) -2-chloro-N- {2- [dimethylamino- (2-nitro-phenyl) -methylcyclohexyl} -benzamide or its hydrochloride
  • (anti, anti) - {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -2-methylbenzamide or its hydrochloride
  • (syn, syn) -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -acetamide or its hydrochloride
  • (syn, syn) -N-2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexylamine or its hydrochloride
  • (anti, anti) -N- {2 - [(2-chloro-phenyl) -dimethyl-amino-methyl] -cyclohexyl} -acetamide or its hydrochloride
  • -2- (syn, anti) (dimethylamino-phenyl-methyl) -cyclohexylamine
  • -N- (syn, anti) [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -benzamide
  • (Anti, anti) -N- {2- [dimethylamino- (2-methoxy-phenyl) -methyl] -cyclohexyl} -benzamide
  • (Anti, anti) -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -benzamide
  • (Anti, anti) -N- {2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexyl} -benzamide
  • (Anti, anti) -N- {2- [dimethylamino- (2-methoxy-phenyl) -methyl] -cyclohexyl} -acetamide
  • (Anti, anti) -2- [dimethylamino- (2-methoxy-phenyl) -methyl] -cyclohexylamine
  • (Anti, anti) -N - {- 2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexyl} -acetamide
  • (Anti, anti) -2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexylamine
  • (Anti, anti) -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -acetamide
  • (Anti, anti) -2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexylamine
  • (Syn, syn) -2- (dimethylamino-phenyl-methyl) -cyclohexylamine
  • (Syn, syn) -2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexylamine
  • (Anti, anti) -2-chloro-N- (3-dimethylamino-1-ethyl-2-methyl-3-phenylpropyl) benzamide
  • (Anti, anti) -3-dimethylamino-1-ethyl-2-methyl-3-phenyl-propylamine
  • (Syn, anti) -2- (dimethylamino-phenyl-methyl) -cyclohexyl-N- (n-propyl) -amine
  • (Syn, anti) -2- (morpholin-4-yl-phenyl-methyl) -cyclohexyl-N- (n-propyl) -amine
  • (Syn, anti) -2, N, N-trimethyl-1,3-diphenyl-N'-propyl-propane-1,3-diamine
  • (Syn, anti) -2- (dimethylamino-phenyl-methyl) -cyclohexyl-N-benzyl-amine
  • (Syn, anti) -2- (morpholin-4-yl-phenyl-methyl) -cyclohexyl-N-benzyl-amine
  • (Syn, anti) -2, N, N-trimethyl-1,3-diphenyl-N'-benzyl-propane-1,3-diamine
  • -2- (syn, anti) (dimethylamino-phenyl-methyl) -cyclohexylamine
  • (Syn, anti) -2- (morpholin-4-yl-phenyl-methyl) -cyclohexylamine
  • (Syn, anti) -2, N, N-trimethyl-1,3-diphenyl-propane-1,3-diamine
  • (Syn, anti) -2 - [(2-chlorophenyl) -dimethylamino-methyl] -cyclohexylamine
  • (Anti, anti) -2 - [(2-chlorophenyl) -dimethylamino-methyl] -cyclohexylamine
  • (Syn, syn) -2- (dimethylamino-phenyl-methyl) -cyclohexylamine
  • -2- (anti, anti) (dimethylamino-phenyl-methyl) -cyclohexylamine
  • (Syn, syn) -2 - [(2-chlorophenyl) -dimethylamino-methyl] -cyclohexylamine
  • (Syn, syn) -2- (dimethylamino-pyridin-3-yl-methyl) -cyclohexylamine
  • (Anti, anti) -2- (dimethylamino-pyridin-3-yl-methyl) cyclohexylamine
  • (Syn, syn) -2- (dimethylamino- (2-methoxyphenyl) -methyl) -cyclohexylamine
  • (Anti, anti) -2- (dimethylamino- (2-methoxyphenyl) -methyl) -cyclohexylamine
  • (Syn, syn) -2- (dimethylamino- (2-nitrophenyl) -methyl) -cyclohexylamine
  • (Anti, anti) -2- (dimethylamino- (2-nitrophenyl) -methyl) -cyclohexylamine
includes.

Ein weiterer Gegenstand der vorliegenden Erfindung sind Verfahren zur Herstellung der Verbindungen der allgemeinen Struktur (l). So können Verbindungen der allgemeinen Struktur (l), in denen R3 für H, n-Propyl oder -CH2-Phenyl steht und R4 für Wasserstoff steht, durch Reduktion des korrespondierenden Imins der allgemeinen Formel (II)

Figure imgb0007
erhalten werden. Geeignete Reduktionsmittel sind beispielsweise komplexe Hydride, wie z.B. ZnCNBH3, das in situ durch Umsetzung von Natriumcyanoborhydrid mit wasserfreiem Zink-(II)-chlorid in einem wasserfreien organischen Lösungsmittel gebildet werden kann, Diisobutylaluminiumhydrid (= DIBAH, DIBAL), L-Selectride (d.h. Lithium-tri-sec.-butylborhydrid) und LiBH4, NaBH4, NaBH3CN und NaBH(OC(=O)CH3)3. Die Reduktion erfolgt dabei bei Temperaturen von - 70 °C bis +65 °C, bevorzugt 0 °C bis +40 °C, über einen Zeitraum von 0,5 h bis 24 h. Dieses Imin-Reduktionsverfahren liefert das Diamin (I) im allgemeinen als ein Gemisch verschiedener denkbarer Stereoisomeren (Diastereomerengemisch). Alternativ kann die Reduktion auch mit Wasserstoff (bei einem H2-Partialdruck von 1 bis 50 bar) in Gegenwart eines geeigneten Übergangsmetall-Katalysators, z.B. Ni, Pd, Pt oder PtO2, bevorzugt in situ, ausgeführt werden.Another object of the present invention are methods for preparing the compounds of general structure (I). Thus, compounds of the general structure (I) in which R 3 is H, n-propyl or -CH 2 -phenyl and R 4 is hydrogen can be obtained by reduction of the corresponding imine of the general formula (II)
Figure imgb0007
 to be obtained. Suitable reducing agents are, for example, complex hydrides, such as ZnCNBH 3 , which can be formed in situ by reacting sodium cyanoborohydride with anhydrous zinc (II) chloride in an anhydrous organic solvent, diisobutylaluminum hydride (= DIBAH, DIBAL), L-Selectride (ie Lithium tri-sec-butylborohydride) and LiBH 4 , NaBH 4 , NaBH 3 CN and NaBH (OC (= O) CH 3 ) 3 . The reduction is carried out at temperatures of - 70 ° C to +65 ° C, preferably 0 ° C to +40 ° C, over a period of 0.5 h to 24 h. This imine reduction process generally provides the diamine (I) as a mixture of various conceivable stereoisomers (Mixture of diastereomers). Alternatively, the reduction can also be carried out with hydrogen (at an H 2 partial pressure of 1 to 50 bar) in the presence of a suitable transition metal catalyst, for example Ni, Pd, Pt or PtO 2 , preferably in situ.

Überraschenderweise wurde gefunden, daß das oben dargelegte Imin-Reduktionsverfahren auch zur diastereoselektiven Synthese von (anti,anti-I) bzw. (syn,syn-I) (mit R3 und R4 = H) angepaßt werden kann: Wird ein Imin (II) mit der relativen Konfiguration anti

Figure imgb0008
mit einem geeigneten Reduktionsmittel, insbesondere Zinkcyanoborhydrid, LiBH4, NaBH4, NaBH3CN oder NaBH(OC(=O)CH3)3 in einem alkoholischen Lösungsmittel umgesetzt, wird mit hoher Stereoselektivität das Diamin (1) mit der relativen Konfiguration anti,anti
Figure imgb0009
 erhalten. Vorzugsweise wird die Reduktion in Methanol unter langsamem Erwärmen von 0 °C auf Raumtemperatur über 8 bis 24 h, insbesondere 10 bis 14 h, durchgeführt.Surprisingly, it has been found that the imine reduction process set out above can also be adapted for the diastereoselective synthesis of (anti, anti-I) or (syn, syn-I) (with R 3 and R 4 = H). II) with the relative configuration anti
Figure imgb0008
 reacted with a suitable reducing agent, in particular zinc cyanoborohydride, LiBH 4 , NaBH 4 , NaBH 3 CN or NaBH (OC (= O) CH 3 ) 3 in an alcoholic solvent, the diamine (1) with the relative configuration of anti, with high stereoselectivity, anti
Figure imgb0009
 receive. The reduction in methanol is preferably carried out with slow heating from 0 ° C. to room temperature over 8 to 24 hours, in particular 10 to 14 hours.

Wird hingegen das Imin (anti-II) mit einem geeigneten Reduktionsmittel in einem etherischen Lösungsmittel umgesetzt, so wird nahezu ausschließlich das Diamin (I) mit der relativen Konfiguration syn,syn erhalten:

Figure imgb0010
If, however, the imine (anti-II) is reacted with a suitable reducing agent in an ethereal solvent, almost exclusively the diamine (I) with the relative configuration syn, syn is obtained:
Figure imgb0010

Vorzugsweise wird diese Reduktion mit L-Selectride oder Diisobutylaluminiumhydrid (DIBAH), insbesondere in THF und unter Erwärmen von 0 °C bis Raumtemperatur über 8 bis 24 h, insbesondere 10 bis 14 h, durchgeführt.This reduction is preferably carried out with L-selectride or diisobutylaluminum hydride (DIBAH), in particular in THF and with heating from 0 ° C. to room temperature over 8 to 24 hours, in particular 10 to 14 hours.

Zur Gewinnung der Diastereomeren des Diamins (I) mit der relativen Konfiguration syn,anti bzw. anti,syn kann das Diastereomerenproduktgemisch des nicht stereoselektiv geführten Imin-Reduktionsverfahrens beispielsweise einer fraktionierten Kristallisation, auch ihrer Salze, oder einer chromatographischen Trennung unterworfen werden.To obtain the diastereomers of diamine (I) having the relative configuration syn, anti or anti, syn, the diastereomeric product mixture of the non-stereoselectively conducted imine reduction process may be subjected to, for example, fractional crystallization, also of its salts, or chromatographic separation.

Die im erfindungsgemäßen nicht stereoselektiven Imin-Reduktionsverfahren eingesetzten Imine der Formel (II) sind aus den entsprechenden Mannich-Basen der allgemeinen Struktur (III)

Figure imgb0011
worin R1, R2, R5, R6 und A wie für Formel (I) und (II) definiert sind, durch Umsetzung mit Ammoniak oder einem äquivalenten Reagenz (wenn R3 in Formel (II) H bedeutet) bzw. mit einem primären Amin R3NH2 (wenn R3 in (II) nicht H, sondern n-Propyl oder-CH2-Phenyl bedeutet) ohne weiteres zugänglich. Für den Fall, daß R3 = H, ist es bevorzugt, die Mannich-Base (III) mit Ammoniumacetat in einem etherischen oder alkoholischen Lösungsmittel zu dem Imin (II) umzusetzen, das seinerseits, vorzugsweise in situ, zur erfindungsgemäßen Verbindung (I) reduziert wird. So kann die Umsetzung von (III) mit Ammoniumacetat in wasserfreiem Tetrahydrofuran (THF) bei Temperaturen von 0 °C bis 80 °C, vorzugsweise bei 20 bis 25 °C und mit einer Reaktionszeit von 0,5 h bis 12 h, vorzugsweise von 30 min bis 120 min, insbesondere 60 min, ausgeführt werden, insbesondere wenn die anschließende Reduktion in THF ausgeführt wird. Alternativ kann die Umsetzung von (III) mit Ammoniumacetat auch in wasserfreiem Methanol bei Temperaturen von 0 °C bis 80 °C, vorzugsweise bei 20 bis 25 °C und mit einer Reaktionszeit von 0,5 h bis 12 h, vorzugsweise von 30 min bis 120 min, insbesondere 60 min, ausgeführt werden, insbesondere wenn die anschließende Reduktion in Methanol ausgeführt wird.The imines of the formula (II) used in the non-stereoselective imine reduction process according to the invention are selected from the corresponding Mannich bases of the general structure (III)
Figure imgb0011
 wherein R 1 , R 2 , R 5 , R 6 and A are as defined for formula (I) and (II), by reaction with ammonia or an equivalent reagent (when R 3 in FIG Formula (II) H) or with a primary amine R 3 NH 2 (when R 3 in (II) is not H, but n-propyl or -CH 2 -phenyl) readily accessible. In the event that R 3 = H, it is preferred to react the Mannich base (III) with ammonium acetate in an ethereal or alcoholic solvent to give the imine (II), which in turn, preferably in situ, to the compound (I) according to the invention is reduced. Thus, the reaction of (III) with ammonium acetate in anhydrous tetrahydrofuran (THF) at temperatures of 0 ° C to 80 ° C, preferably at 20 to 25 ° C and with a reaction time of 0.5 h to 12 h, preferably from 30 min to 120 min, in particular 60 min, are carried out, especially if the subsequent reduction is carried out in THF. Alternatively, the reaction of (III) with ammonium acetate in anhydrous methanol at temperatures from 0 ° C to 80 ° C, preferably at 20 to 25 ° C and with a reaction time of 0.5 h to 12 h, preferably from 30 min to 120 min, in particular 60 min, are carried out, especially if the subsequent reduction is carried out in methanol.

Analog sind die anti-konfigurierten Imine (anti-II) ausgehend von den entsprechenden anti-konfigurierten Mannich-Basen (anti-III)

Figure imgb0012
zugänglich, indem diese mit dem primären Amin R3NH2 bzw. mit Ammoniak oder einem äquivalenten Reagenz, wie z.B. Ammoniumacetat, unter den für die Bildung von (II) oben angegebenen Bedingungen umgesetzt werden.Analogously, the anti-configured imines (anti-II) are derived from the corresponding anti-configured Mannich bases (anti-III)
Figure imgb0012
 accessible by reacting these with the primary amine R 3 NH 2 or with ammonia or an equivalent reagent, such as ammonium acetate, under the conditions given for the formation of (II) above.

Die Herstellung der Mannichbasen (III) ist an sich literaturbekannt und wird z.B. in den Patentanmeldungen EP 1 043 307 A2 und EP 1 043 306 A2, die hiermit in die Offenbarung der vorliegenden Erfindung einbezogen werden, ausführlich dargestellt. So führt die 1,4-Addition sekundärer Amine HNR5R6 an Enone der allgemeinen Struktur (XI) - die ihrerseits durch Aldolkondensation von Ketonen der Formel (IX) mit Aldehyden der allgemeinen Formel (X) erhalten werden - zu den gewünschten Mannich-Basen (II) (US-Patent 4,017,637), die in der Regel als Gemisch der Stereoisomeren anfallen.

Figure imgb0013
The preparation of the Mannich bases (III) is known per se from the literature and is described, for example, in the patent applications EP 1 043 307 A2 and EP 1 043 306 A2, which are incorporated herein by reference are hereby incorporated in detail in the disclosure of the present invention. Thus, the 1,4-addition of secondary amines HNR 5 R 6 to enones of the general structure (XI) - which in turn are obtained by aldol condensation of ketones of the formula (IX) with aldehydes of the general formula (X) - leads to the desired Mannich Bases (II) (US Patent 4,017,637), which are generally obtained as a mixture of stereoisomers.
Figure imgb0013

Die Bedeutung der Reste R1, R2, R5, R6 und A entspricht der Bedeutung für die Formeln (I) und (II).The meaning of the radicals R 1 , R 2 , R 5 , R 6 and A corresponds to the meaning for the formulas (I) and (II).

Die so gewonnenen Mannich-Basen (III) können als Gemisch der Stereoisomeren verwendet oder unter Einsatz von im Stand der Technik wohlbekannten Verfahren, wie z.B. Kristallisation oder Chromatographie, in ihre Diastereoisomeren aufgetrennt und als solche umgesetzt werden.The Mannich bases (III) so obtained may be used as a mixture of the stereoisomers or may be prepared using techniques well known in the art, e.g. Crystallization or chromatography, separated into their diastereoisomers and reacted as such.

Alternativ können Mannich-Basen mit vorzugsweise anti-Konfiguration diastereoselektiv durch Umsetzung von Enaminen der allgemeinen Struktur (XII), worin die Reste R z.B. Alkyl bedeuten oder zusammen -(CH2)4- oder -(CH2)5- bilden, mit Iminiumsalzen der allgemeinen Struktur (VIII), in der Z⊖ ein geeignetes Gegenion, wie z.B. Cl⊖, Br⊖, I⊖ oder AlCl4 ⊖, bedeutet, hergestellt werden (EP 1 043 307 A2 und EP 1 043 306 A2).

Figure imgb0014
Alternatively, Mannich bases of preferably anti-diastereoselective configuration can be prepared by reacting enamines of general structure (XII) wherein the radicals R are, for example, alkyl or together form - (CH 2 ) 4 - or - (CH 2 ) 5 - with iminium salts of the general structure (VIII) in which Z ⊖ is a suitable counterion such as Cl ⊖ , Br ⊖ , I ⊖ or AlCl 4 ⊖ , prepared (EP 1 043 307 A2 and EP 1 043 306 A2).
Figure imgb0014

Die Enamine werden nach literaturbekannten Verfahren aus Ketonen der allgemeinen Struktur (IX) und sekundären Aminen, z.B. Dimethylamin, Pyrrolidin, Piperidin oder Morpholin, hergestellt (Acta Chem. Scand. B 38 (1984) 49-53). Die Iminiumsalze (VIII) werden nach literaturbekannten Verfahren z.B. durch Umsetzung von Aminalen der allgemeinen Struktur (XIII) mit Säurechloriden, z.B. Acetylchlorid oder Thionylchlorid (Houben-Weyl - Methoden der Organischen Chemie, E21 b (1995) 1925-1929), oder durch Umsetzung von Aldehyden der Formel (X) mit sekundären Aminen in Gegenwart von Natriumiodid, Trimethylsilyliodid und Triethylamin hergestellt (Synlett (1997) 974-976). Die Iminiumsalze (VIII) müssen dabei nicht isoliert werden, sondern können auch in situ erzeugt und mit den Enaminen der Formel (XII) bevorzugt zu den anti-Mannich-Basen (anti-III) umgesetzt werden (Angew. Chem. 106 (1994) 2531-2533). Es ist auch möglich, Ketone der allgemeinen Struktur (IX) direkt mit Iminiumsalzen (VIII) zu Mannich-Basen (III) umzusetzen. Auch in diesem Fall werden bevorzugt die Mannich-Basen (anti-III) mit anti-Konfiguration gebildet.The enamines are prepared by methods known in the literature from ketones of the general structure (IX) and secondary amines, e.g. Dimethylamine, pyrrolidine, piperidine or morpholine (Acta Chem. Scand. B 38 (1984) 49-53). The iminium salts (VIII) are prepared by literature methods, e.g. by reacting amines of general structure (XIII) with acid chlorides, e.g. Acetyl chloride or thionyl chloride (Houben-Weyl - Methods of Organic Chemistry, E21b (1995) 1925-1929), or by reacting aldehydes of the formula (X) with secondary amines in the presence of sodium iodide, trimethylsilyl iodide and triethylamine (Synlett (1997) 974-976). The iminium salts (VIII) need not be isolated, but can also be generated in situ and reacted with the enamines of the formula (XII) preferably to the anti-Mannich bases (anti-III) (Angew Chem 106 (1994) 2531-2533). It is also possible to react ketones of the general structure (IX) directly with iminium salts (VIII) to Mannich bases (III). Also in this case, the Mannich bases (anti-III) having anti-configuration are preferably formed.

Aus den anti-konfigurierten Mannich-Basen (anti-III) können, falls erforderlich, auch die entsprechenden syn-konfigurierten Isomeren (syn-III) dadurch gewonnen werden, daß die Mannich-Base (anti-III) in einem geeigneten Lösungsmittel, z.B. einem Alkohol, wie Methanol oder Ethanol, oder Wasser, gelöst, mit einer hinreichend starken Säure, z.B. wäßrige Salzsäure, verdünnte Schwefelsäure oder konz. Essigsäure, versetzt und etwa 8 bis 24 h gerührt wird; dabei ist es für die gewünschte Epimerisierung wesentlich, daß die gelöste Mannich-Base (III) nicht aus der Lösung ausfällt oder auskristallisiert, sondern in Lösung bleibt. Nach dem Entfernen des Lösungsmittels werden die anti-Mannich-Base (anti-III) und die syn-Mannich-Base (syn-III) als Diastereomerengemisch, zumeist in einem Verhältnis von 1 :1, erhalten, das nach herkömmlichen Methoden (Kristallisation, Chromatographie) aufgetrennt werden kann.If necessary, the corresponding syn-configured isomers (syn-III) can also be obtained from the anti-configured Mannich bases (anti-III) by reacting the Mannich base (anti-III) in a suitable solvent, eg an alcohol such as methanol or ethanol, or water, dissolved with a sufficiently strong acid, for example aqueous hydrochloric acid, dilute sulfuric acid or conc. Acetic acid, and stirred for about 8 to 24 hours; It is essential for the desired epimerization that the dissolved Mannich base (III) does not precipitate or crystallize out of the solution, but remains in solution. After removal of the solvent, the anti-Mannich base (anti-III) and the syn-Mannich base (syn-III) as a mixture of diastereomers, usually in a ratio of 1: 1, obtained by conventional methods (crystallization, Chromatography) can be separated.

Ein weiteres erfindungsgemäßes Verfahren zur Herstellung der erfindungsgemäßen Verbindungen der allgemeinen Struktur (I); in denen R3 und R4 jeweils H bedeuten, geht von einem Aminoalkohol der allgemeinen Struktur (IV) aus, der in einem Verfahrensschritt (a) in das korrespondierende Mesylat bzw. Tosylat der Formel (V), worin L Mesyl (CH3SO2-) oder Tosyl (4-CH3-Phenyl-SO2-) bedeutet, beispielsweise durch Umsetzung von (IV) mit Mesylchlorid (CH3SO2Cl) bzw. Tosylchlorid (p-Toluolsulfonsäurechlorid, 4-CH3-Phenyl-SO2Cl) in Gegenwart einer Base (z.B. Triethylamin), überführt wird; anschließend wird das Mesilat bzw. Tosylat (V) in einem Verfahrensschritt (b) beispielsweise mit Natriumazid zu dem Azid (VI) umgesetzt, welches in einem Verfahrensschritt (c) unter Reduktion in das erfindungsgemäße Diamin der Formel (I) überführt wird. Die Reduktion erfolgt hierbei nach literaturbekannten Verfahren, z.B. mit Natriumborhydrid in Gegenwart katalytischer Mengen Cobalt-(II)-bromid (D. M. Tschaen et al., J. Org. Chem. (1995) 60, 4324-4330) oder mit Lithiumaluminiumhydrid in Diethylether.Another inventive method for preparing the compounds of general structure (I) according to the invention; in which R 3 and R 4 are each H, is based on an aminoalcohol of the general structure (IV), in a process step (a) in the corresponding mesylate or tosylate of the formula (V) wherein L mesyl (CH 3 SO 2 -) or tosyl (4-CH 3 -phenyl-SO 2 -), for example by reaction of (IV) with mesyl chloride (CH 3 SO 2 Cl) or tosyl chloride (p-toluenesulfonyl chloride, 4-CH 3 -phenyl) SO 2 Cl) in the presence of a base (eg triethylamine) is transferred; Subsequently, the mesilate or tosylate (V) is reacted in a process step (b), for example with sodium azide to the azide (VI), which is converted in a process step (c) with reduction in the novel diamine of the formula (I). The reduction takes place here by literature methods, for example with sodium borohydride in the presence of catalytic amounts of cobalt (II) bromide (Tschaen T et al., J. Org. Chem. (1995) 60, 4324-4330) or with lithium aluminum hydride in diethyl ether.

Dieses Verfahren kann auch so angewandt werden, daß eine erfindungsgemäße Verbindung der Formel (I) bevorzugt in einer bestimmten relativen Konfiguration erhalten wird. Geht man von einem Aminoalkohol der allgemeinen Struktur (anti,anti-IV) - ein Aminoalkohol (IV) mit der relativen Konfiguration (anti,anti) - aus, so verläuft der Verfahrensschritt (a') bevorzugt unter Erhalt der relativen Stereochemie zu der Verbindung (anti,anti-V), während die anschließende Azidbildung (b') unter Inversion der Konfiguration des Stereozentrums am O-L-Kohlenstoff Atom verläuft und somit das Azid (syn,anti-V1) ergibt. Die anschließende Reduktion von (syn,anti-VI) ergibt das Diamin (syn,anti-I).

Figure imgb0015
Figure imgb0016
 This method can also be applied so that a compound of the formula (I) according to the invention is preferably obtained in a certain relative configuration. Assuming an aminoalcohol of the general structure (anti, anti-IV) - an aminoalcohol (IV) having the relative configuration (anti, anti) -, process step (a ') preferably proceeds to give the relative stereochemistry to the compound (anti, anti-V), while the subsequent azide formation (b ') proceeds by inversion of the configuration of the stereocenter at the OL carbon atom, thus giving the azide (syn, anti-V1). Subsequent reduction of (syn, anti-VI) yields the diamine (syn, anti-I).
Figure imgb0015
Figure imgb0016

Entsprechend ist auch das Diamin (anti,anti-I) stereoselektiv zugänglich, wenn man das erfindungsgemäße Verfahren mit einem Aminoalkohol der allgemeinen Struktur (syn.anti-IV) beginnt und über das Mesylat bzw. Tosylat der allgemeinen Struktur (syn,anti-V) zu dem Azid der allgemeinen Struktur (anti,anti-VI) führt, das abschließend zum Diamin (anti,anti-1) reduziert wird.Accordingly, the diamine (anti, anti-I) is stereoselectively accessible when starting the process of the invention with an amino alcohol of the general structure (syn.anti-IV) and on the mesylate or tosylate of the general structure (syn, anti-V ) leads to the azide of the general structure (anti, anti-VI), which is finally reduced to the diamine (anti, anti-1).

Die in diesem Verfahren eingesetzten Aminoalkohole der Formel (IV) sind gemäß EP 0 143 306 A2 ausgehend von den entsprechenden Mannich-Basen (III) durch Reduktion mit einem Reduktionsmittel, wie z.B. Natriumborhydrid, Natriumcyanoborhydrid, Lithiumaluminiumhydrid, Düsobutylaluminiumhydrid oder einem komplexen Analogon dieser Verbindungen, bei -70 bis +110 °C in geeigneten Lösungsmitteln, z.B. Diethylether, THF, Methanol oder Ethanol, erhältlich. Geht man beispielsweise von einer Mannich-Base mit anti-Konfiguration (anti-III) aus, so wird bei Reduktion mit NaBH4 in Ethanol bei Raumtemperatur und einer Reaktionszeit von 8 bis 16h der entsprechende (anti, anti-IV) Aminoalkohol erhalten. Wird hingegen zur Reduktion der Mannich-Base (anti-III) DIBAH oder L-Selectride in THF verwendet, so erhält man den (syn,anti-IV)-Aminoalkohol ih-ticiher-Diastereomerenreinheit. Bei Reduktion einer Mannich-Base (III), die nicht in diastereomerenreiner oder -angereicherter Form vorliegt, wird üblicherweise eine Mischung der verschiedenen Stereoisomeren des Aminoalkohols (IV) erhalten, die - falls erforderlich - mit bekannten Methoden (Kristalisation, Chromatographie) in die Diastereomeren und ggf. auch die Enantiomeren aufgetrennt werden kann.The aminoalcohols of the formula (IV) used in this process are, according to EP 0 143 306 A2, starting from the corresponding Mannich bases (III) by reduction with a reducing agent such as, for example, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutylaluminum hydride or a complex analog of these compounds, at -70 to +110 ° C in suitable solvents, for example diethyl ether, THF, methanol or ethanol, available. If one starts, for example, from a Mannich base with anti-configuration (anti-III), the corresponding (anti, anti-IV) amino alcohol is obtained on reduction with NaBH 4 in ethanol at room temperature and a reaction time of 8 to 16 h. If, however, to reduce the Mannich base (anti-III) DIBAH or L-Selectride used in THF, we obtain the (syn, anti-IV) amino alcohol ih-ticiher diastereomeric purity. Upon reduction of a Mannich base (III) which is not in diastereomerically pure or enriched form, a mixture of the various stereoisomers of the aminoalcohol (IV) is usually obtained, which - if necessary - into the diastereomers by known methods (crystallization, chromatography) and optionally also the enantiomers can be separated.

Alternativ zu dem Tosyl/Mesyl-Azid-Verfahren kann der Aminoalkohol (IV) auch mittels Mitsunobu-Reaktion durch Umsetzung zunächst mit Azodicarbonsäuredimethyl- oder -diethylester, Triphenylphosphan und einem Phthalimid und anschließend mit Hydrazin in das korresponidierende Diamin (1) überführt werden (O. Mitsunobu, Synthesis (1981) 1-28). Da diese Reaktion unter Inversion der Stereochemie am O-Kohlenstoffatom abläuft, kann mit ihrer Hilfe aus dem Alkohol (anti,anti-IV) stereoselektiv das Diamin (syn,anti-I), aus (syn,anti-IV) hingegen stereoselektiv das Diamin (anti,anti-I) erhalten werden.As an alternative to the tosyl / mesyl-azide process, the aminoalcohol (IV) can also be converted into the corresponding diamine (1) by Mitsunobu reaction by reaction first with dimethyl or diethyl azodicarboxylate, triphenylphosphane and a phthalimide and then with hydrazine Mitsunobu, Synthesis (1981) 1-28). Since this reaction proceeds by inversion of the stereochemistry at the O-carbon atom, the diamine (syn, anti-I) can be stereoselected from the alcohol (anti, anti-IV), while the diamine can be stereoselected from (syn, anti-IV) (anti, anti-I) can be obtained.

In einem weiteren erfindungsgemäßen Verfahren werden Verbindungen der allgemeinen Struktur (I) mit R3 = H, n-Propyl oder -CH2-Phenyl und R4 H - und zwar bevorzugt die Diasteromeren (syn,anti-I) (mit der relativen Konfiguration syn,anti) erhalten -, das durch folgende Verfahrensschritte gekennzeichnet ist:

  • (aa) Umsetzung eines Imins der allgemeinen Struktur (VII)
    Figure imgb0017
     worin R1 und R2 wie für Formel (I) definiert sind und R3 H, n-Propyl oder -CH2-Phenyl bedeutet,
    mit einem Iminiumsalz der allgemeinen Struktur (VIII)
    Figure imgb0018
     worin R5, R6, A und Z⊖ wie oben definiert sind; und
  • (bb) anschließende Reduktion des oder der in dem Verfahrensschritt (aa) gebildeten Zwischenprodukts/e. Vorzugsweise erfolgt die Reduktion mit einem komplexen Hydrid oder mit molekularem Wasserstoff (H2-Partialdruck von 1 bis 50 bar) in Gegenwart eines Übergangsmetall-Katalysators (Ni, Pd, Pt, PtO2).
In a further inventive method, compounds of general structure (I) with R 3 = H, n-propyl or -CH 2 -phenyl and R 4 H - and preferably the diastereomers (syn, anti-I) (with the relative configuration syn, anti) - which is characterized by the following process steps:
  • (aa) reaction of an imine of the general structure (VII)
    Figure imgb0017
     wherein R 1 and R 2 are as defined for formula (I) and R 3 is H, n-propyl or -CH 2 -phenyl,
    with an iminium salt of the general structure (VIII)
    Figure imgb0018
     wherein R 5 , R 6 , A and Z ⊖ are as defined above; and
  • (bb) subsequent reduction of the intermediate (s) formed in process step (aa). Preferably, the reduction is carried out with a complex hydride or with molecular hydrogen (H 2 partial pressure of 1 to 50 bar) in the presence of a transition metal catalyst (Ni, Pd, Pt, PtO 2 ).

Geeignete komplexe Hydride sind z.B. Natriumborhydrid, Natriumcyanoborhydrid, Lithiumaluminiumhydrid, Düsobutytaluminiumhydrid oder ein komplexes Analogon dieser Verbindungen, die bei -70 bis +110 °C in geeigneten Lösungsmitteln, z.B. Diethylether, THF, Methanol oder Ethanol, ggf. im Gemisch mit Methylenchlorid, eingesetzt werden können.Suitable complex hydrides are e.g. Sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutyraluminum hydride, or a complex analogue of these compounds which may be used at -70 to +110 ° C in suitable solvents, e.g. Diethyl ether, THF, methanol or ethanol, optionally in admixture with methylene chloride, can be used.

Die Imine (VII) sind ausgehend von den entsprechenden Ketonen (IX) durch Umsetzung mit Ammoniak oder Ammoniumacetat (R3 = H) bzw primären Aminen R3NH2 (R3≠ H) nach literaturbekannten Verfahren erhältlich (J. March, Advanced Organic Chemistry, New York, Chichester, Brisbane, Toronto, Singapore, 3. Aufl., (1985), S. 796-798).The imines (VII) are obtained starting from the corresponding ketones (IX) by reaction with ammonia or ammonium acetate (R 3 = H) or primary amines R 3 NH 2 (R 3 ≠ H) by literature methods (J. March, Advanced Organic Chemistry, New York, Chichester, Brisbane, Toronto, Singapore, 3rd ed., (1985), pp. 796-798).

Wird bei diesem (Imin+Iminiumsalz)-Verfahren ein Imin (VII) verwendet, für das R3 -(CH2)-Phenyl bedeutet, handelt es sich also bei dem Imin (VII) um ein N-Benzyl-substitulertes Imin, so kann dieser Benzylrest im erfindungsgemäßen Produkt (I) mit R3 = Benzyl durch Umsetzung mit Wasserstoff (H2) in Gegenwart eines Übergangmetalls (z.B. Palladium, Platin oder Nickel) entfernt und so das Diamin (I) mit R3 = R4 = H erhalten werden. Dieser Verfahrensschritt (cc) wird vorzugsweise mit 10% Palladium an Kohlenstoff als Übergangmetall, bevorzugt in Methanol, ausgeführt.If an imine (VII) is used in this (imine + iminium salt) process, for which R 3 is - (CH 2 ) -phenyl, then the imine (VII) is an N-benzyl-substituted imine, see above this benzyl radical in the product (I) according to the invention with R 3 = benzyl by reaction with Removing hydrogen (H 2 ) in the presence of a transition metal (eg palladium, platinum or nickel) and thus the diamine (I) with R 3 = R 4 = H are obtained. This process step (cc) is preferably carried out with 10% palladium on carbon as transition metal, preferably in methanol.

Mit diesem erfindungsgemäßen Verfahren sind somit auch syn,anti-konfigurierte Diamine der allgemeinen Struktur (I) diastereoselektiv zugänglich.Syn, anti-configured diamines of the general structure (I) are thus diastereoselectively accessible with this process according to the invention.

Verbindungen der allgemeinen Struktur (I) mit R3 = H und R4 = H können - unabhängig davon, ob sie als Racemat, in Form eines oder mehrerer Diastereomeren oder eines oder mehrerer Enantiomeren vorliegen - durch Umsetzung mit einem Acylierungsreagenz in die korrespondierenden Verbindungen der allgemeinen Struktur (I) mit R3 = C(=O)-R7 überführt werden, wobei R7 wie oben definiert ist. Vorzugsweise ist das Acylierungsmittel ein Säurechlorid der allgemeinen Formel R7-C(=O)-Cl, worin R7 Methyl, Phenyl, 2-Fluorphenyl, 2-Chlorphenyl oder 2-Methylphenyl bedeutet.Compounds of general structure (I) with R 3 = H and R 4 = H can - regardless of whether they are present as a racemate, in the form of one or more diastereomers or one or more enantiomers - by reaction with an acylating reagent in the corresponding compounds of general structure (I) with R 3 = C (= O) -R 7 , wherein R 7 is as defined above. Preferably, the acylating agent is an acid chloride of the general formula R 7 -C (= O) -Cl, wherein R 7 is methyl, phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-methylphenyl.

In literaturbekannter Weise können die Verbindungen der allgemeinen Struktur (I) mit R3 = H und R4 = H auch alkyliert oder einer reduktiven Aminierung mit Aldehyden oder Ketonen (s. z.B. J. March, Advanced Organic Chemistry, New York, Chichester, Brisbane, Toronto, Singapore, 3. Aufl., (1985), 798-800) unterworfen werden, so daß die entsprechenden Verbindungen (l), in denen R3 n-Propyl oder -CH2-Phenyl und R4 H bedeutet, ohne weiteres zugänglich sind. Diamine der allgemeinen Struktur (l) mit R3 = H können dann ebenfalls einer Acylierung (so daß R3 -C(=O)-R7 bedeutet) unterworfen werden, vorzugsweise mit einem wie oben definierten Säurechlorid Cl-C(=O)-R7.In the manner known from the literature, the compounds of general structure (I) can also be alkylated with R 3 = H and R 4 = H or a reductive amination with aldehydes or ketones (see, for example J. March, Advanced Organic Chemistry, New York, Chichester, Brisbane, Toronto , Singapore, 3rd ed., (1985), 798-800), so that the corresponding compounds (I) in which R 3 is n-propyl or -CH 2 -phenyl and R 4 is H readily accessible are. Diamines of the general structure (I) where R 3 = H can then likewise be subjected to an acylation (so that R 3 is -C (= O) -R 7 ), preferably with an acid chloride Cl-C (= O) as defined above. -R 7 .

Die erfindungsgemäßen Verbindungen der allgemeinen Formel (l), in denen der Rest R3 gleich n-Propyl oder -CH2-Phenyl ist und R4 = H bedeutet, sind beispielsweise auch durch Umsetzung des entsprechenden Imins, das in Form seines tautomeren Enamins (XII) vorliegt, mit einem entsprechenden Iminiumsalz (VIII) und anschließender Reduktion mit beispielsweise NaBH4 in Methanol zugänglich (Synlett (1997) 177-178).

Figure imgb0019
The compounds according to the invention of the general formula (I) in which the radical R 3 is n-propyl or -CH 2 -phenyl and R 4 = H means, for example, by reaction of the corresponding imine, which is in the form of its tautomeric enamine (XII), with a corresponding iminium salt (VIII) and subsequent reduction with, for example, NaBH 4 in methanol accessible (Synlett (1997) 177-178).
Figure imgb0019

Dabei entsteht bevorzugt das syn,anti-Diastereomere der Verbindung (I).In this case, the syn, anti-diastereomer of the compound (I) is preferably formed.

Die in den zur Herstellung der erfindungsgemäßen Diamine der allgemeinen Struktur (I) verwendeten Verfahren eingesetzten Ausgangsverbindungen, Reagenzien und Lösungsmittel sind, soweit in der Beschreibung nichts anderes angegeben ist, kommerziell erhältlich (von Acros, Geel; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka, Seelze; Lancaster, Mülheim; Maybridge, Tintagel; Merck, Darmstadt; Sigma, Deisenhofen; TCI, Japan) oder können nach im Stand der Technik allgemein bekannten Verfahren hergestellt werden.The starting compounds, reagents and solvents used in the processes used to prepare the diamines of the general structure (I) according to the invention are commercially available (from Acros, Geel, Avocado, Port of Heysham, Aldrich, Deisenhofen), unless otherwise specified in the description Fluka, Seelze, Lancaster, Mülheim, Maybridge, Tintagel, Merck, Darmstadt, Sigma, Deisenhofen, TCI, Japan) or may be prepared by methods well known in the art.

Die erfindungsgemäßen Verbindungen der allgemeinen Struktur (I) können sowohl in Substanz als auch als Salz isoliert werden. Die erfindungsgemäße Verbindung der allgemeinen Struktur (I) wird üblicherweise nach erfolgter Umsetzung gemäß dem oben beschriebenen erfindungsgemäßen Verfahren und anschließender herkömmlicher Aufarbeitung erhalten. Die so gewonnene oder in-situ ohne Isolierung gebildete Verbindung der allgemeinen Struktur (I) kann dann beispielsweise durch Umsetzung mit einer anorganischen oder organischen Säure, vorzugsweise mit Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, p-Toluolsulfonsäure, Kohlensäure, Ameisensäure, Essigsäure, Oxalsäure, Bernsteinsäure, Weinsäure, Mandelsäure, Fumarsäure, Milchsäure. Citronensäure, Glutaminsäure oder Aspaginsäure, in das korrespondierende Salz überführt werden. Bei den gebildeten Salzen handelt es sich u.a. um Hydrochloride, Hydrobromide, Phosphate, Carbonate, Hydrogencarbonate, Formiate, Acetate, Oxalate, Succinate, Tartrate, Fumarate, Citrate und Glutaminate. Die besonders bevorzugte Hydrochloridbildung kann auch durch Versetzen der in einem geeigneten organischen Lösungsmittel, wie z.B. Butan-2-on (Methylethylketon), gelösten Base mit Trimethylsilylchlorid (TMSCl), vorteilhaft in Gegenwart von Wasser, herbeigeführt werden.The compounds of the general structure (I) according to the invention can be isolated both in substance and as a salt. The compound of the general structure (I) according to the invention is usually obtained after the reaction according to the above-described inventive method and subsequent conventional work-up. The compound of general structure (I) thus obtained or obtained in situ without isolation can then be, for example, by reaction with an inorganic or organic acid, preferably hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic and acetic acid . Oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid. Citric acid, glutamic acid or aspartic acid are converted into the corresponding salt. The salts formed include hydrochlorides, hydrobromides, phosphates, carbonates, bicarbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutaminates. The most preferred hydrochloride formation may also be accomplished by the reaction of the base dissolved in a suitable organic solvent such as butan-2-one (methyl ethyl ketone) with trimethylsilyl chloride (TMSCl), advantageously in the presence of water.

Soweit die Verbindungen der allgemeinen Struktur (I) in dem erfindungsgemäßen Herstellungsverfahren als Racemate oder als Mischungen ihrer verschiedenen Enantiomeren und/oder Diastereomeren erhalten werden, können diese Mischungen nach im Stand der Technik wohlbekannten Verfahren aufgetrennt werden. Geeignete Methoden sind u. a. chromatographische Trennverfahren, insbesondere Flüssigkeitschromatographie-Verfahren unter Normal- oder erhöhtem Druck, bevorzugt MPLC- und HPLC-Verfahren, sowie Verfahren der fraktionierten Kristallisation. Dabei können insbesondere einzelne Enantiomeren z.B. mittels HPLC an chiraler Phase oder mittels Kristallisation von mit chiralen Säuren, etwa (+)-Weinsäure, (-)-Weinsäure oder (+)-10-Camphersulfonsäure, gebildeten diastereomeren Salzen voneinander getrennt werden.As far as the compounds of general structure (I) are obtained in the production process according to the invention as racemates or as mixtures of their different enantiomers and / or diastereomers, these mixtures can be separated by methods well-known in the art. Suitable methods are u. a. chromatographic separation processes, in particular liquid chromatography processes under normal or elevated pressure, preferably MPLC and HPLC processes, and fractional crystallization processes. In particular, single enantiomers, e.g. by chiral phase HPLC or by crystallization of diastereomeric salts formed with chiral acids such as (+) - tartaric acid, (-) - tartaric acid or (+) - 10-camphorsulfonic acid.

Ein weiterer Gegenstand der vorliegenden Erfindung ist ein Arzneimittel, enthaltend mindestens eine wie oben definierte Verbindung der allgemeinen Struktur (I), oder eines ihrer pharmazeutischen Salze, insbesondere das Hydrochlorid-Salz. Vorzugsweise enthält das erfindungsgemäße Arzneimittel in einer pharmazeutischen Zusammensetzung mindestens eine der oben beispielhaft genannten Verbindungen in Substanz oder als pharmazeutisch annehmbares Salz und gegebenenfalls weitere Wirk- und Hilfsstoffe. Dabei kann das erfindungsgemäße Diamin (I) als Racemat, in Form eines oder mehrerer Diastereomeren oder eines oder mehrerer Enantiomeren vorliegen.Another object of the present invention is a pharmaceutical composition comprising at least one compound of general structure (I) as defined above, or one of its pharmaceutical salts, in particular the hydrochloride salt. Preferably, the pharmaceutical composition according to the invention contains in a pharmaceutical composition at least one of the above exemplified compounds in substance or as a pharmaceutically acceptable salt and optionally other active ingredients and excipients. It can do that Inventive diamine (I) as a racemate, in the form of one or more diastereomers or one or more enantiomers.

Da sich die erfindungsgemäßen Verbindungen der allgemeinen Struktur (I) überraschend als analgetisch wirksam erwiesen haben, werden die sie enthaltenden erfindungsgemäßen Arzneimittel vorzugsweise in der Prophylaxe und/oder Therapie von Schmerzzuständen, wie z. B. akuter Schmerz, chronischer Schmerz bzw. neuropathischer Schmerz, insbesondere starker bis stärkster Schmerzen, eingesetzt. Es hat sich auch gezeigt, daß die erfindungsgemäßen Arzneimittel zur Behandlung und/oder Prophylaxe von Diarrhoe, Harninkontinenz, Juckreiz und/oder Tinnitus aurium eingesetzt werden können.Since the compounds of general structure (I) according to the invention have surprisingly been found to be analgesic effective, the medicaments containing them according to the invention are preferably in the prophylaxis and / or treatment of pain conditions, such. As acute pain, chronic pain or neuropathic pain, especially strong to severe pain used. It has also been shown that the medicaments according to the invention can be used for the treatment and / or prophylaxis of diarrhea, urinary incontinence, itching and / or tinnitus aurium.

Ein weiterer Gegenstand der vorliegenden Erfindung betrifft die Verwendung eines Diamins der Formel (I) oder eines seiner pharmazeutisch annehmbaren Salze zur Herstellung eines Medikaments zur Prophylaxe und/oder Behandlung von Schmerz, Diarrhoe, Harninkontinenz, Juckreiz und/oder Tinnitus aurium.Another object of the present invention relates to the use of a diamine of the formula (I) or one of its pharmaceutically acceptable salts for the manufacture of a medicament for the prophylaxis and / or treatment of pain, diarrhea, urinary incontinence, itching and / or tinnitus aurium.

Die erfindungsgemäßen Arzneimittel, Medikamente und pharmazeutischen Zusammensetzungen können als flüssige, halbfeste oder feste Arzneiformen und in Form von z.B. Injektionslösungen, Tropfen, Säften, Sirupen, Sprays, Suspensionen, Granulaten, Tabletten, Pellets, transdermale therapeutische Systeme, Kapseln, Pflastern, Zäpfchen, Salben, Cremes, Lotionen, Gelen, Emulsionen oder Aerosolen vorliegen und verabreicht werden und enthalten neben mindestens einer erfindungsgemäßen Verbindung der allgemeinen Struktur (I) je nach galenischer Form und in Abhängigkeit vom Applikationsweg pharmazeutische Hilfsstoffe, wie z.B. Trägermaterialien, Füllstoffe, Lösungsmittel, Verdünnungsmittel, oberflächenaktive Stoffe, Farbstoffe, Konservierungsstoffe, Sprengmittel, Gleitmittel, Schmiermittel, Aromen und/oder Bindemittel. Diese Hilfsstoffe können beispielsweise sein: Wasser, Ethanol, 2-Propanol, Glycerin, Ethylenglycol, Propylenglycol, Polyethylenglycol, Polypropylenglycol, Glucose, Fructose, Lactose, Saccharose, Dextrose, Melasse, Stärke, modifizierte Stärke, Gelatine, Sorbitol, Inositol, Mannitol, mikrokristalline Cellulose, Methylcellulose, Carboxymethylcellulose, Celluloseacetat, Schellack, Cetylalkohol, Polyvinylpyrrolidon, Paraffine, Wachse, natürliche und synthetische Gummis, Akaziengummi, Alginate, Dextran, gesättigte und ungesättigte Fettsäuren, Stearinsäure, Magnesiumstearat, Zinkstearat, Glycerylstearat, Natriumlaurylsulfat, genießbare Öle, Sesamöl, Kökusnußöl, Erdnußöl, Sojabohnenöl, Lecithin, Natriumlactat, Polyoxyethylen- und -propylenfettsäureester, Sorbitanfettsäureester, Sorbinsäure, Benzoesäure, Citronensäure, Ascorbinsäure, Tanninsäure, Natriumchlorid, Kaliumchlorid, Magnesiumchlorid, Calciumchlorid, Magnesiumoxid, Zinkoxid, Siliciumdioxid, Titanoxid, Titandioxid, Magnesiumsulfat, Zinksulfat, Calciumsulfat, Pottasche, Calciumphosphat, Dicalciumphosphat, Kaliumbromid, Kaliumiodid, Talkum, Kaolin, Pectin, Crospovidon, Agar und Bentonit.The medicaments, medicaments and pharmaceutical compositions according to the invention can be in the form of liquid, semisolid or solid dosage forms and in the form of, for example, injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, pellets, transdermal therapeutic systems, capsules, patches, suppositories, ointments , Creams, lotions, gels, emulsions or aerosols are present and administered and in addition to at least one compound of general structure (I) depending on galenic form and depending on the route of application pharmaceutical excipients, such as support materials, fillers, solvents, diluents, surface-active Fabrics, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and / or binders. These adjuvants may be, for example: Water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, Cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic gums, acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, kosnut nut oil, peanut oil, soybean oil, lecithin , Sodium lactate, polyoxyethylene and -propylene fatty acid esters, sorbitan fatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, Potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidone, agar and bentonite.

Die Auswahl der Hilfsstoffe sowie die einzusetzenden Mengen derselben hängt davon ab, ob das Arzneimittel/Medikament oral, subkutan, parenteral, intravenös, vaginal, pulmonal, intraperitoneal, transdermal, intramuskulär, nasal, buccal, rectal oder örtlich, zum Beispiel auf Infektionen an der Haut, der Schleimhäute und an den Augen, appliziert werden soll. Für die orale Applikation eignen sich u.a. Zubereitungen in Form von Tabletten, Dragees, Kapseln, Granulaten, Tropfen, Säften und Sirupen, für die parenterale, topische und inhalative Applikation Lösungen, Suspensionen, leicht rekonstituierbare Pulver zur Inhalation sowie Sprays. Erfindungsgemäße Verbindungen der allgemeinen Struktur (I) in einem Depot in gelöster Form oder in einem Pflaster, gegebenenfalls unter Zusatz von die Hautpenetration fördernden Mitteln, sind geeignete perkutane Applikationszubereitungen. Rektal, transmucosal, parenteral, oral oder perkutan anwendbare Zubereitungsformen können die erfindungsgemäßen Verbindungen der allgemeinen Struktur (I) verzögert freisetzen.The choice of excipients and the amounts to be used depend on whether the medicinal product / drug is administered orally, subcutaneously, parenterally, intravenously, vaginally, pulmonarily, intraperitoneally, transdermally, intramuscularly, nasally, buccally, rectally or locally, for example at infections on the skin Skin, the mucous membranes and the eyes, should be applied. For oral administration are, inter alia, preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups, for parenteral, topical and inhalative administration solutions, suspensions, easily reconstitutable powder for inhalation and sprays. Compounds of the general structure (I) according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents, are suitable percutaneous administration preparations. Rectal, transmucosal, parenteral, oral or Percutaneously applicable preparation forms can release the compounds of the general structure (I) according to the invention with a delay.

Die Herstellung der erfindungsgemäßen Arzneimittel und pharmazeutischen Zusammensetzungen erfolgt mit Hilfe von im Stand der Technik der pharmazeutischen Formulierung wohlbekannten Mitteln, Vorrichtungen, Methoden und Verfahren, wie sie beispielsweise in "Remington's Pharmaceutical Sciences", Hrsg. A.R. Gennaro, 17. Ed., Mack Publishing Company, Easton, Pa. (1985), insbesondere in Teil 8, Kapitel 76 bis 93, beschrieben sind.The preparation of the pharmaceutical and pharmaceutical compositions of the present invention is accomplished by means well known in the art of pharmaceutical formulation, devices, methods and methods, as described, for example, in "Remington's Pharmaceutical Sciences", ed. A.R. Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa. (1985), especially in Part 8, Chapters 76 to 93.

So kann z.B. für eine feste Formulierung, wie eine Tablette, der Wirkstoff des Arzneimittels, d.h. eine Verbindung der allgemeinen Struktur (I) oder eines ihrer pharmazeutisch annehmbaren Salze, mit einem pharmazeutischen Träger, z.B. herkömmlichen Tabletteninhaltsstoffen, wie Maisstärke, Lactose, Saccharose, Sorbitol, Talkum, Magnesiumstearat, Dicalciumphosphat oder pharmazeutisch akzeptable Gummis, und pharmazeutischen Verdünnungsmitteln, wie z.B. Wasser, granuliert werden, um eine feste Zusammensetzung zu bilden, die eine erfindungsgemäße Verbindung oder ein pharmazeutisch annehmbares Salz davon in homogener Verteilung enthält. Unter einer homogenen Verteilung wird hier verstanden, daß der Wirkstoff gleichmäßig über die gesamte Zusammensetzung verteilt ist, so daß diese ohne weiteres in gleich wirksame Einheitsdosis-Formen, wie Tabletten, Pillen oder Kapseln, unterteilt werden kann. Die feste Zusammensetzung wird anschließend in Einheitsdosis-Formen unterteilt. Die Tabletten oder Pillen des erfindungsgemäßen Arzneimittels bzw. der erfindungsgemäßen Zusammensetzungen können auch überzogen oder auf andere Weise kompoundiert werden, um eine Dosisform mit verzögerter Freisetzung bereitzustellen. Geeignete Beschichtungsmittel sind u. a. polymere Säuren und Mischungen von polymeren Säuren mit Materialien wie z.B. Schellack, Cetylalkohol und/oder Celluloseacetat. Die an den Patienten zu verabreichende Wirkstoffmenge variiert und ist abhängig vom Gewicht, dem Alter und der Krankheitsgeschichte des Patienten, sowie von der Applikationsart, der Indikation und dem Schweregrad der Erkrankung. Üblicherweise werden 0,005 bis 500 mg/kg, insbesondere 0,05 bis 5 mg/kg, vorzugsweise 2 bis 250 mg/kg Körpergewicht wenigstens einer erfindungsgemäßen Verbindung der allgemeinen Struktur (I) appliziert.Thus, for example, for a solid formulation, such as a tablet, the active ingredient of the drug, ie a compound of general structure (I) or one of its pharmaceutically acceptable salts, may be combined with a pharmaceutical carrier, eg conventional tablet ingredients, such as corn starch, lactose, sucrose, sorbitol , Talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, such as water, to form a solid composition containing a compound of the invention or a pharmaceutically acceptable salt thereof in homogeneous distribution. By homogeneous distribution it is meant herein that the active ingredient is distributed evenly throughout the composition so that it can be readily subdivided into equally effective unit dose forms such as tablets, pills or capsules. The solid composition is then subdivided into unit dose forms. The tablets or pills of the drug or compositions of the invention may also be coated or otherwise compounded to provide a sustained release dosage form. Suitable coating agents include polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and / or cellulose acetate. The amount of drug to be administered to the patient varies and depends on the weight, age and history of the patient, as well as the route of administration, the indication and the severity of the disease. Usually, 0.005 to 500 mg / kg, in particular 0.05 to 5 mg / kg, preferably 2 to 250 mg / kg body weight of at least one compound of the general structure (I) according to the invention are applied.

Nachfolgend wird die vorliegende Erfindung durch Beispiele weiter erläutert, ohne sie darauf zu beschränken.Hereinafter, the present invention will be further explained by examples without being limited thereto.

BeispieleExamples VorbemerkungenPreliminary remarks

Die eingesetzten Chemikalien und Lösungsmittel wurden von Acros, Geel; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka, Seelze; Lancaster, Mülheim; Maybridge, Tintagel; Merck, Darmstadt; Sigma, Deisenhofen bzw. TCI, Japan durch Kauf erworben oder nach üblichen und im Stand der Technik bekannten Verfahren synthetisiert.The chemicals and solvents used were from Acros, Geel; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka, Seelze; Lancaster, Mülheim; Maybridge, Tintagel; Merck, Darmstadt; Sigma, Deisenhofen or TCI, Japan purchased by purchase or synthesized by conventional and known in the art.

Wasserfreies THF wurde frisch über Kalium unter einer Argon-Atmosphäre destilliert.Anhydrous THF was freshly distilled over potassium under an argon atmosphere.

Dünnschichtchromatographische Untersuchungen wurden mit HPTLC-Fertigplatten, Kieselgel 60 F 254, der Firma E. Merck, Darmstadt, durchgeführt. Als stationäre Phase für die Säulenchromatographie und MPLC wurde Kieselgel 60 (0.040 - 0.063 mm) der Firma E. Merck, Darmstadt, oder Al2O3, neutral, der Firma Macherey-Nagel, Düren, eingesetzt.Thin-layer chromatographic investigations were carried out with HPTLC precast plates, Kieselgel 60 F 254, E. Merck, Darmstadt. Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt, or Al 2 O 3 , neutral, from Macherey-Nagel, Düren, was used as the stationary phase for the column chromatography and MPLC.

Die Ausbeuten der hergestellten Verbindungen sind nicht optimiert. Alle angegebenen Temperaturen sind unkorrigiert.The yields of the compounds produced are not optimized. All indicated temperatures are uncorrected.

Die Mischungsverhältnisse der Laufmittel für chromatographische Untersuchungen sind stets in Volumen/Volumen (V/V) angegeben.The mixing ratios of the eluents for chromatographic investigations are always given in volume / volume (V / V).

ESI-Massenspektren wurden aufgenommen mit einem LCQ Classic Massenspektrometer der Firma Finnigan, die 1H- und 13C-NMR-Spektren wurden mit einem 300-(75-)MHz- Avance-DPX-300-NMR-Gerät, einem 600-(150-)MHz-Avance-DRX-600-NMR-Gerät oder einem Bruker-ARX-200-NMR-Gerät der Firma Bruker aufgenommen, wobei Tetramethylsilan als interner Standard verwendet wurde. IR-Spektren wurden mit einem Nicolet 510 P FT-IR Spektrometer aufgenommen. GC/MS-Daten wurden mit einem Finnigan MAT Magnum System 240-Gerät erhalten. Elementaranatysen , wurden, soweit durchgeführt, mit einem Perkin Elmer Elemental Analyser durchgeführt und lieferten hinreichende Elementaranalysen-Ergebnisse: C ± 0.34, H ± 0.28, N ± 0.19.ESI mass spectra were recorded on a LCQ Classic mass spectrometer from Finnigan, the 1 H and 13 C NMR spectra were recorded on a 300 (75) MHz Avance DPX 300 NMR instrument, a 600- ( 150-) MHz Avance DRX-600 NMR instrument or a Bruker ARX 200 NMR instrument from Bruker, using tetramethylsilane as the internal standard. IR spectra were recorded on a Nicolet 510P FT-IR spectrometer. GC / MS data was obtained on a Finnigan MAT Magnum System 240 instrument. Elemental analyzes were carried out with a Perkin Elmer Elemental Analyzer and provided adequate elemental analysis results: C ± 0.34, H ± 0.28, N ± 0.19.

Allgemeine Arbeitsvorschrift 1 (AAV 1: Imin+Iminiumsalz-Verfahren)General Procedure 1 (AAV 1: imine + iminium salt method)

Die Reaktionen wurden unter einer Argon-Atmosphäre ausgeführt. Eine Lösung des Imins (VII) (2,5 mmol) in wasserfreiem CH2Cl2 (2,5 mL) wurde auf -80 °C abgekühlt. Das Iminiumsalz (VIII) (2,5 mmol) wurde dann unter Rühren in einer Portion hinzugegeben. Die Mischung wurde gerührt, und man ließ die Temperatur über 2-3 h auf -30 °C ansteigen. Die Reaktionsmischung wurde für 15 h bei dieser Temperatur in einem Tiefkühlgerät aufbewahrt. Dann wurde NaBH4 (40 mmol) in MeOH (10 mL) hinzugegeben, und man ließ die Temperatur auf Raumtemperatur ansteigen. Nach 5-stündigem Rühren bei Umgebungstemperatur wurde HCl (5 mL, 6 N) hinzugegeben, und die Mischung wurde einige Male mit Et2O gewaschen. Anschließend wurden die wäßrige Schicht durch Zugabe von NH3 (25 % NH3: H2O =1:1) alkalisch gemacht und das erfindungsgemäße Diamin (I) mit CH2Cl2 (3 x 50 mL) extrahiert. Die vereinigten organischen Phasen wurden über Na2SO4 getrocknet. Das Lösungsmittel wurde an einem Rotationsverdampfer entfernt, und der Rückstand wurde mittels Säulenchromatographie an Al2O3 (CH2Cl2 /MeOH) gereinigt. Die letzte eluierte Fraktion war das Diamin (I).The reactions were carried out under an argon atmosphere. A solution of the imine (VII) (2.5 mmol) in anhydrous CH 2 Cl 2 (2.5 mL) was cooled to -80 ° C. The iminium salt (VIII) (2.5 mmol) was then added in one portion with stirring. The mixture was stirred and the temperature was allowed to rise to -30 ° C over 2-3 h. The reaction mixture was stored for 15 hours at this temperature in a freezer. Then NaBH 4 (40 mmol) in MeOH (10 mL) was added and the temperature allowed to rise to room temperature. After stirring at ambient temperature for 5 h, HCl (5 mL, 6N) was added and the mixture was washed several times with Et 2 O. Subsequently, the aqueous layer was rendered alkaline by adding NH 3 (25% NH 3 : H 2 O = 1: 1) and the diamine (I) according to the invention was extracted with CH 2 Cl 2 (3 × 50 ml). The The combined organic phases were dried over Na 2 SO 4 . The solvent was removed on a rotary evaporator and the residue was purified by column chromatography on Al 2 O 3 (CH 2 Cl 2 / MeOH). The last eluted fraction was the diamine (I).

Allgemeine Arbeitsvorschrift 2 (AAV 2: Debenzylierung des Diamins (I) mit R3 = -CHGeneral Procedure 2 (AAV 2: Debenzylation of the diamine (I) with R 3 = -CH 22 -Phenyl)phenyl)

Eine Lösung des benzylierten Diamins (I) in wasserfreiem MeOH (10 mL) wurde bei Raumtemperatur in Gegenwart von 10 % Pd / C(20 mg) gerührt, und H2 wurde in die Mischung eingeleitet, bis die Debenzylierung vollständig war (DC-Kontrolle). Nach Entfernen des Katalysators mittels Filtration über Celite wurde das Filtrat eingedampft, um das debenzylierte Diamin (I) zu ergeben. Der Rückstand wurde mittels Säulenchromatographie an Al2O3 (CH2Cl2 / MeOH = 95 : 5) gereinigt.A solution of the benzylated diamine (I) in anhydrous MeOH (10 mL) was stirred at room temperature in the presence of 10% Pd / C (20 mg) and H 2 was introduced into the mixture until debenzylation was complete (TLC control ). After removing the catalyst by filtration through Celite, the filtrate was evaporated to give the debenzylated diamine (I). The residue was purified by column chromatography on Al 2 O 3 (CH 2 Cl 2 / MeOH = 95: 5).

Allgemeine Arbeitsvorschrift 3 (AAV 3: Azid-Methode)General Working Procedure 3 (AAV 3: Azide Method) Herstellung der Mannich-Basen (III)Production of the Mannich bases (III)

Zu einer Lösung von wasserfreiem Nal (getrocknet bei 140°C im Vakuum) in trockenem MeCN (5,5 mmol; c ≈ 1 mol/l) wurden Dimethylamin-Hydrochlorid (2,5 mmol), NEt3 (5 mmol) und Me3SiCl (5,5 mmol) hinzugegeben. Nach Rühren für 30 min bei Umgebungstemperatur wurde der Aldehyd A-CHO (2,5 mmol) hinzugegeben, und das Rühren wurde für weitere 30 min fortgesetzt. Dann wurde als Enamin 1-(Pyrrolidino)-1-cyclohexen (2,5 mmol) hinzugegeben, und die Mischung wurde für weitere 60 min gerührt. Danach wurde die Mischung mit wäßr. HCl (5 mL, 37 % HCl : H2O = 1 : 1) angesäuert, für 10 min gerührt und mit Et2O (3 x 50 mL) gewaschen. Anschließend wurde verdünnter NH3 (25 mL, 25 % NH3 : H2O = 1 : 4) unter heftigem Rühren hinzugegeben, und die Mannich-Base (III) wurde mit CH2Cl2 oder Et2O (3 x 50 mL) extrahiert. Die vereinigten organischen Phasen wurden über Na2SO4 getrocknet. Das Lösungsmittel 2 wurde schließlich an einem Rotationsverdampfer ohne Erwärmen entfernt.To a solution of anhydrous Nal (dried at 140 ° C in vacuo) in dry MeCN (5.5 mmol, c ≈ 1 mol / l) was added dimethylamine hydrochloride (2.5 mmol), NEt 3 (5 mmol) and Me 3 SiCl (5.5 mmol) was added. After stirring for 30 min at ambient temperature, the aldehyde A-CHO (2.5 mmol) was added and stirring was continued for a further 30 min. Then, as the enamine, 1- (pyrrolidino) -1-cyclohexene (2.5 mmol) was added and the mixture was stirred for an additional 60 minutes. Thereafter, the mixture was washed with aq. HCl (5 mL, 37% HCl: H 2 O = 1: 1), stirred for 10 min, and washed with Et 2 O (3 x 50 mL). Subsequently, dilute NH 3 (25 mL, 25% NH 3 : H 2 O = 1: 4) was added with vigorous stirring and the Mannich base (III) was quenched with CH 2 Cl 2 or Et 2 O (3 x 50 mL ) extracted. The combined organic phases were dried over Na 2 SO 4 . Solvent 2 was finally removed on a rotary evaporator without heating.

Herstellung der Aminoalkohole (IV)Preparation of the amino alcohols (IV)

Die Mannich-Base (III) (1 mmol) wurde in Ethanol 10 mL) gelöst, NaBH4 (2,5 mmol) wurde hinzugegeben, und die Mischung wurde für 5 h bei Raumtemperatur gerührt. Anschließend wurde wäßr. HCl (37 % HCl : H2O = 1 : 1, 10 mL) hinzugegeben, und die Mischung wurde einige Male mit Et2O (50 mL) gewaschen. Die wäßrige Schicht wurde durch Zugabe von NH3 (25 % NH3 : H2O = 1 : 1) alkalisch gemacht. Das Produkt wurde mit CH2Cl2 (3 x 50 mL) extrahiert, und die organische Phase wurde über Na2SO4 getrocknet. Das Lösungsmittel wurde im Vakuum entfernt, um ein gelbes Öl zu erhalten. Das Produkt (IV) wurde ohne weitere Reinigung verwendet.The Mannich base (III) (1 mmol) was dissolved in ethanol (10 mL), NaBH 4 (2.5 mmol) was added, and the mixture was stirred for 5 h at room temperature. Subsequently, aq. HCl (37% HCl: H 2 O = 1: 1, 10 mL) and the mixture was washed several times with Et 2 O (50 mL). The aqueous layer was made alkaline by addition of NH 3 (25% NH 3 : H 2 O = 1: 1). The product was extracted with CH 2 Cl 2 (3 x 50 mL) and the organic phase was dried over Na 2 SO 4 . The solvent was removed in vacuo to give a yellow oil. The product (IV) was used without further purification.

Mesylierung des Aminoalkohols (IV)Mesylation of the aminoalcohol (IV)

Zu einer Lösung des Aminoalkohols (IV) (2 mmol) in CH2Cl2 (5 mL) wurden bei 0°C Mesylchlorid (2,4 mmol) und NEt3 (3 mmol) hinzugegeben. Nach 1 h war die Reaktion vollständig (DC-Kontrolle). Die Mischung wurde mit CH2Cl2 (10 mL) verdünnt und zweimal mit wäßr. Na2CO3-Lösung und einmal mit Salzlösung gewaschen. Die organische Phase wurde mit Na2SO4 getrocknet, um das Mesylat (V) als ein gelbes Öl zu ergeben, das in den nachfolgenden Reaktionen ohne weitere Reinigung eingesetzt wurde.To a solution of the aminoalcohol (IV) (2 mmol) in CH 2 Cl 2 (5 mL) at 0 ° C was added mesyl chloride (2.4 mmol) and NEt 3 (3 mmol). After 1 h, the reaction was complete (TLC control). The mixture was diluted with CH 2 Cl 2 (10 mL) and washed twice with aq. Na 2 CO 3 solution and washed once with brine. The organic phase was dried with Na 2 SO 4 to give the mesylate (V) as a yellow oil which was used in subsequent reactions without further purification.

Bildung des Azids (VI)Formation of the azide (VI)

Eine Lösung von NaN3 (20 mmol) und des Mesylats (V) (2 mmol) in DMSO (40 mL) wurde für 3 h auf 50°C erhitzt. Das DC zeigte den vollständigen Verbrauch des Ausgangsmaterials. Die Reaktion wurde mit Salzlösung gequencht und mit CH2Cl2 (50 mL) extrahiert. Die organische Phase wurde dreimal mit gesättigter Na2CO3-Lösung und einmal mit Salzlösung gewaschen. Nach dem Trocknen über Na2SO4 wurde das Azid (VI) als ein braunes Öl erhalten. Das rohe Produkt (VI) wurde ohne weitere Reinigung in der folgenden Reaktion eingesetzt.A solution of NaN 3 (20 mmol) and the mesylate (V) (2 mmol) in DMSO (40 mL) was heated to 50 ° C for 3 h. The DC showed the complete consumption of the starting material. The reaction was quenched with brine and extracted with CH 2 Cl 2 (50 mL). The organic phase was washed three times with saturated Na 2 CO 3 solution and once with brine. After drying over Na 2 SO 4 , the azide (VI) was obtained as a brown oil. The crude product (VI) was used without further purification in the following reaction.

Reduktion des Azids (VI) zum Diamin (I)Reduction of the azide (VI) to the diamine (I)

Eine Lösung des Azids (VI) (1 mmol) in Et2O wurde langsam zu einer Suspension von LiAlH4 (1,5 mmol) in Et2O hinzugegeben. Nach 4 h wurde die Reaktion sehr langsam mit Wasser und HCl (37 % HCl: H2O = 1 : 1) gequencht. Nach dem Alkalischmachen wurde das Produkt mit Et2O (3 x 50 mL) extrahiert und mit Wasser (50 mL) gewaschen. Die organische Phase wurde mit Na2SO4 getrocknet und an Al2O3 (CH2Cl2 / MeOH = 95 : 5) chromatographiert, um das Diamin (I) als ein gelbliches Öl zu ergeben.A solution of the azide (VI) (1 mmol) in Et 2 O was added slowly to a suspension of LiAlH 4 (1.5 mmol) in Et 2 O. After 4 h, the reaction was quenched very slowly with water and HCl (37% HCl: H 2 O = 1: 1). After basification, the product was extracted with Et 2 O (3 x 50 mL) and washed with water (50 mL). The organic phase was dried with Na 2 SO 4 and chromatographed on Al 2 O 3 (CH 2 Cl 2 / MeOH = 95: 5) to give the diamine (I) as a yellowish oil.

Allgemeine Arbeitsvorschrift 4 (AAV 4; Aminoimin(II)-Reduktions-Verfahren) Variante (A)General Working Instructions 4 (AAV 4, Aminoimine (II) Reduction Process) Variant (A)

Eine Lösung von Ammoniumacetat (12,1 mmol) und der Mannich-Base (III) (1,8 mmol) in THF wurde für 1 h bei Raumtemperatur gerührt. Eine Lösung von L-Selectride in THF (3,6 mmol) wurde bei 0°C hinzugegeben, man ließ die Temperatur auf Raumtemperatur ansteigen und rührte weiter über Nacht. HCl (5 mL, 6 N) wurde hinzugegeben und die Mischung einige Male mit Et2O gewaschen. Anschließend wurde die wäßrige Phase mit NH3 (25 % NH3 : H2O = 1 : 1) alkalisch gemacht, und das Diamin (I)wurde mit CH2Cl2 (3 x 50 mL) extrahiert. Die vereinigten organischen Phasen wurden über Na2SO4 getrocknet. Das Lösungsmittel wurde an einem Rotationsverdampfer entfernt, und der Rückstand wurde mittels Säulenchromatographie an Al2O3 (CH2Cl2 / MeOH) gereinigt. Die letzte eluierte Fraktion war das Diamin (I).A solution of ammonium acetate (12.1 mmol) and the Mannich base (III) (1.8 mmol) in THF was stirred for 1 h at room temperature. A solution of L-Selectride in THF (3.6 mmol) was added at 0 ° C, the temperature was allowed to rise to room temperature and stirring continued overnight. HCl (5 mL, 6N) was added and the mixture was washed several times with Et 2 O. Subsequently, the aqueous phase was made alkaline with NH 3 (25% NH 3 : H 2 O = 1: 1) and the diamine (I) was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic phases were dried over Na 2 SO 4 . The solvent was removed on a rotary evaporator and the residue was purified by column chromatography on Al 2 O 3 (CH 2 Cl 2 / MeOH). The last eluted fraction was the diamine (I).

Variante BVariant B

Eine Lösung von Ammoniumacetat (12,1 mmol) und der Mannich-Base (III) (1,8 mmol) in THF wurde für 1 h bei Raumtemperatur gerührt. Eine Lösung von DIBAH in n-Hexan (3,6 mmol) wurde bei 0°C hinzugegeben. Man ließ die Temperatur auf Raumtemperatur ansteigen und rührte weiter über Nacht. HCl (5 mL, 6 N) wurde hinzugegeben und die Mischung einige Male mit Et2O gewaschen. Anschließend wurden die wäßr. Phase durch Zugabe von NH3 (25% NH3:H2O = 1 : 1) alkalisch gemacht und das Diamin (I) mit CH2Cl2 (3 x 50 ml) extrahiert. Die vereinigten organischen Phasen wurden über Na2SO4 getrocknet. Das Lösungsmittel wurde an einem Rotationsverdampfer entfernt und der Rückstand mittels Säulenchromatographie an Al2O3 (CH2Cl2 / MeOH) gereinigt. Die letzte eluierte Fraktion war das Diamin (I).A solution of ammonium acetate (12.1 mmol) and the Mannich base (III) (1.8 mmol) in THF was stirred for 1 h at room temperature. A solution of DIBAH in n-hexane (3.6 mmol) was added at 0 ° C. The temperature was allowed to rise to room temperature and stirring continued overnight. HCl (5 mL, 6 N) was added and the mixture several times washed with Et 2 O. Subsequently, the aq. Phase by addition of NH 3 (25% NH 3 : H 2 O = 1: 1) and the diamine (I) extracted with CH 2 Cl 2 (3 x 50 ml). The combined organic phases were dried over Na 2 SO 4 . The solvent was removed on a rotary evaporator and the residue was purified by column chromatography on Al 2 O 3 (CH 2 Cl 2 / MeOH). The last eluted fraction was the diamine (I).

Variante CVariant C

NaCNBH3 (2,1 mmol) wurde zu einer Suspension von ZnCl2 in MeOH bei 0°C hinzugegeben. Nach Rühren für 1 h bei dieser Temperatur wurden die Männich-Base (III) (1,8 mmol) und Ammoniumacetat (12,1 mmol) in einer Portion hinzugegeben. Die Mischung wurde gerührt und man ließ die Temperatur auf Raumtemperatur ansteigen. Es wurde weiter über Nacht gerührt. HCl (5 mL, 6 N) wurde hinzugegeben und die Mischung einige Male mit Et2O gewaschen. Anschließend wurden die wäßrige Phase durch Zugabe von NH3 (25 % NH3 : H2O = 1 : 1) alkalisch gemacht und das Diamin (I) mit CH2Cl2 (3 x 50 mL) extrahiert. Die vereinigten organischen Phasen wurden über Na2SO4 getrocknet. Das Lösungsmittel wurde an einem Rotationsverdampfer entfernt, und der Rückstand wurde mittels Säulenchromatographie an Al2O3 (CH2Cl2 / MeOH) gereinigt. Die letzte eluierte Fraktion war das Diamin (I).NaCNBH 3 (2.1 mmol) was added to a suspension of ZnCl 2 in MeOH at 0 ° C. After stirring for 1 h at this temperature, the Mannich base (III) (1.8 mmol) and ammonium acetate (12.1 mmol) were added in one portion. The mixture was stirred and the temperature allowed to rise to room temperature. It was kept stirring overnight. HCl (5 mL, 6N) was added and the mixture was washed several times with Et 2 O. Subsequently, the aqueous phase was rendered alkaline by adding NH 3 (25% NH 3 : H 2 O = 1: 1) and the diamine (I) was extracted with CH 2 Cl 2 (3 × 50 mL). The combined organic phases were dried over Na 2 SO 4 . The solvent was removed on a rotary evaporator and the residue was purified by column chromatography on Al 2 O 3 (CH 2 Cl 2 / MeOH). The last eluted fraction was the diamine (I).

Allgemeine Arbeitsvorschrift 5 (AAV 5; Acylierungsverfahren)General working procedure 5 (AAV 5, acylation procedure)

Das Reaktionsgefäß wurde im Trockenschrank ausgeheizt. Das Diamin (I) (mit R3 = R4 = H) (600 mg) wurde vorgelegt, und eine Lösung von 1,3 Moläquivalenten Triethylamin in Dichlormethan (V/V = 1 : 8), die eine Spur 4-Dimethylaminopyridin enthielt, wurde zugegeben. Anschließend wurden 1,3 Moläquivalente des Säurechlorids R7-C(=O)-Cl bei -10 °C zugegeben und über Nacht unter Erwärmung auf Raumtemperatur gerührt. Nach erneuter Abkühlung bis -10°C wurden 2 ml 5 N KOH-Losung zugegeben, die Phasen getrennt und die organische Phase nochmals mit 4 ml 0,1 N KOH-Lösung gewaschen. Die organische Phase wurde über Magnesiumsulfat getrocknet und bei 40 °C im Vakuum eingeengt. Das erhaltene Rohprodukt wurde über MPLC (Fließmittel n-Hexan; allmählicher Zusatz von Diethylether auf bis zu 100%) aufgereinigt. Die abschließende Hydrochloridfällung erfolgte durch Lösen der Rohbase in ca. 10 ml 2-Butanon je Gramm Base, anschließende Zugabe eines halben Moläquivalents Wasser, gefolgt von 1,1 Moläquivalenten Chlortrimethylsilan und Rühren über Nacht. Das ausgefallene Hydrochlorid wurde abfiltriert und im Vakuum getrocknet.The reaction vessel was baked in a drying oven. The diamine (I) (with R 3 = R 4 = H) (600 mg) was initially charged and a solution of 1.3 molar equivalents of triethylamine in dichloromethane (V / V = 1: 8) containing one lane of 4-dimethylaminopyridine , was added. Subsequently, 1.3 molar equivalents of the acid chloride R 7 -C (= O) -Cl at -10 ° C was added and stirred overnight while warming to room temperature. After renewed cooling to -10 ° C, 2 ml of 5 N KOH solution were added, the phases were separated and the organic phase again with 4 ml of 0.1 N KOH solution washed. The organic phase was dried over magnesium sulfate and concentrated at 40 ° C in vacuo. The crude product obtained was purified by MPLC (eluent n-hexane, gradual addition of diethyl ether up to 100%). The final hydrochloride precipitation was carried out by dissolving the crude base in about 10 ml of 2-butanone per gram of base, then adding half a molar equivalent of water followed by 1.1 molar equivalents of chlorotrimethylsilane and stirring overnight. The precipitated hydrochloride was filtered off and dried in vacuo.

Allgemeine Arbeitsvorschrift 6 (AAV 6; Hydrochlorid-Bildung)General procedure 6 (AAV 6, hydrochloride formation)

Zur Hydrochlorid-Fällung wurde die Rohbase (I) in ca. 10 ml 2-Butanon je Gramm Base aufgenommen. Dann wurden 0,5 Moläquivalente Wasser, gefolgt von 1,1 Moläquivalenten Chlortrimethylsilan hinzugegeben und über Nacht gerührt. Das ausgefallene Hydrochlorid wurde abfiltriert und im Vakuum getrocknet.For hydrochloride precipitation, the crude base (I) was taken up in about 10 ml of 2-butanone per gram of base. Then, 0.5 molar equivalents of water, followed by 1.1 molar equivalents of chlorotrimethylsilane were added and stirred overnight. The precipitated hydrochloride was filtered off and dried in vacuo.

Die nach den AAV 1-6 beispielhaft hergestellten Verbindungen sind in Tabelle 1 wiedergegeben. Die Bestimmung der Stereochemie erfolgte mittels 1H- und 13C-NMR-Untersuchungen, insbesondere durch Vergleich der chemischen Verschiebungen der C-Atome C-NR3R4, C-R1 und C-A im 13C-NMR-Spektrum der erfindungsgemäßen Verbindungen untereinander und mit den Verschiebungen der entsprechenden C-Atome im 13C-NMR-Spektrum von (anti,anti)-1-Hydroxy-2-(pyrrolidin-phenyl-methyl)-cyclohexan und (syn,anti)-1-Hydroxy-2-(pyrrolidin-phenyl-methyl)-cyclohexan. Tabelle 1 Beispiels-Nr. Verbindung Herstellungsverfahren (AAV) 1 (syn,syn)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]benzamid-Hydrochlorid 4A/B + 5 + 6 1a (syn,syn)-2-(Dimethylaminopyridin-3-ylmethyl)cyclohexylamin 4A/B 2 (syn,syn)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-fluorbenzamid-Hydrochlorid 4A/B + 5 + 6 3 (syn,syn)-2-Chlor-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-benzamid-Hydrochlorid 4A/B + 5 + 6 4 (syn,syn)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-methylbenzamid-Hydrochlorid 4A/B + 5 + 6 5 (anti,anti)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-benzamid-Hydrochlorid 4C + 5 + 6 5a (anti,anti)-2-(Dimethylaminopyridin-3-ylmethyl)cyclohexylamin 4C 6 (anti,anti)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclo-hexyl]-2-fluorbenzamid-Hydrochlorid 4C + 5 + 6 7 (anti,anti)-2-Chlor-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]benzamid-Hydrochlorid 4C + 5 + 6 8 (anti,anti)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-methylbenzamid-Hydrochlorid 4C + 5 + 6 9 (syn,syn)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]acetamid-Hydrochlorid 4A/B + 5 + 6 10 (anti,anti)-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]acetamid-Hydrochlorid 4C + 5 + 6 11 (syn,syn)-N-[2-(Dimethylaminophenylmethyl)cyclohexyl]-2-fluorbenzamid-Hydrochlorid 4A/B + 5 + 6 11a (syn,syn)-2-(Dimethylaminophenylmethyl)cyclohexylamin 4A/B 12 (syn,syn)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-acetamid-Hydrochlorid 4A/B+5+6 13 (syn,syn)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-benzamid-Hydrochlorid 4A/B+5+6 14 (syn,syn)-2-Chlor-N-[2-(dimethylamino-phenyl-methyl)-cyclohexyl]-benzamid-Hydrochlorid 4A/B + 5 + 6 15 (syn,syn)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-2-methyl-benzamid-Hydrochlorid 4A/B + 5 + 6 16 (anti,anti)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-acetamid-Hydrochlorid 4C + 5 + 6 16a (anti,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin 4C 17 (anti,anti)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-benzamid-Hydrochlorid 4C + 5 + 6 18 (anti,anti)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-2-methyl-benzamid-Hydrochlorid 4C + 5 + 6 19 (syn,syn)-2-Chlor-N-{2-[(2-chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-benzamid-Hydrochlorid 4A/B + 5 + 6 19a (syn,syn)-2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexylamin 4A/B 20 (anti,anti)-2-Chlor-N-{2-[(2-chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-benzamid-Hydrochlorid 4C + 5 + 6 20a (anti,anti)-2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexylamin 4C 21 (syn,syn)-N-{2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-2-fluor-benzamid-Hydrochlorid 4A/B + 5 + 6 22 (anti,anti)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-benzamid-Hydrochlorid 4C + 5 + 6 22a (anti,anti)-2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexylamin 4C 23 (anti,anti)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-2-fluor-benzamid-Hydrochlorid 4C + 5 + 6 24 (anti,anti)-2-Chlor-N-{2-[dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-benzamid-Hydrochlorid 4C + 5 + 6 25 (anti,anti)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-2-methyl-benzamid-Hydrochlorid 4C + 5 + 6 26 (syn,syn)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-acetamid-Hydrochlorid 4A/B + 5 + 6 26a (syn,syn)-N-2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexylamin 4A/B 27 (anti,anti)-N-{2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-acetamid-Hydrochlorid 4C + 5 + 6 28 (syn,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin 1 + 2 29 (syn,anti)-N-[2-(Dimethylamino-phenyl-methyl)-cyclohexyl]-benzamid 1 30 (anti,anti)-N-{2-[Dimethylamino-(2-methoxy-phenyl)-methyl]-cyclohexyl}-benzamid 4C + 5 30a (anti,anti)-2-[Dimethylamino-(2-methoxy-phenyl)-methyl]-cyclohexylamin 4C 31 (anti,anti)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-benzamid 4C + 5 33 (anti,anti)-N-{2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-benzamid 4C + 5 35 (anti,anti)-N-{2-[Dimethylamino-(2-methoxy-phenyl)-methyl]-cyclohexyl}-acetamid 4C + 5 36 (anti,anti)-{2-[(2-Chlor-phenyl)-dimethylamino-methyl]-cyclohexyl}-acetamid 4C + 5 37 (anti,anti)-N-{2-[Dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-acetamid 4C + 5 38 (syn,syn)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin 4A/B 40 (anti,anti)-2-Chlor-N-(3-dimethylamino-1-ethyl-2-methyl-3-phenyl-propyl)-benzamid 4C + 5 40a (anti,anti)-3-Dimethylamino-1 -ethyl-2-methyl-3-phenyl-propylamin 4C 41 (syn,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexyl-N-(n-propyl)-amin 1 42 (syn,anti)-2-(Morpholin-4-yl-phenyl-methyl)-cyclohexyl-N-(n-propyl)-amin 1 43 (syn,anti)-2,N,N-Trimethyl-1,3-diphenyl-N'-propy-propan-1,3-diamin 1 44 (syn,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexyl-N-benzyl-amin 1 45 (syn,anti)-2-(Morpholin-4-yl-phenyl-methyl)-cyclohexyl-N-benzyl-amin 1 46 (syn,anti)-2,N,N-Trimethyl-1,3-diphenyl-N'-benzyl-propan-1,3-diamin 1 47 (syn,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin 1 + 2; 3 48 (syn,anti)-2-(Morpholin-4-yl-phenyl-methyl)-cyclohexylamin 1+2 49 (syn,anti)-2,N,N-Trimethyl-1,3-diphenyl-propan-1,3-diamin 1+2 50 (syn,anti)-2-[(2-Chlorphenyl)-dimethylamino-methyl]-cyclohexylamin 3 51 (anti,anti)-2-[(2-Chlorphenyl)-dimethylamino-methyl]-cyclohexylamin 4C 52 (syn,syn)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin 4A/B 53 (anti,anti)-2-(Dimethylamino-phenyl-methyl)-cyclohexylamin 4C 54 (syn,syn)-2-[(2-Chtorphenyl)-dimethylamino-methyl]-cyclohexylamin 4A/B 55 (syn,syn)-2-(Dimethylamino-pyridin-3-yl-methyl)-cyclohexylamin 4A/B 56 (anti,anti)-2-(Dimethylamino-pyridin-3-yl-methyl)-cyclohexylamin 4C 57 (syn,syn)-2-(Dimethylamino-(2-methoxyphenyl)-methyl)-cyclohexylamin 4A/B 58 (ant,anti)-2-(Dimethylamino-(2-methoxyphenyl)-methyl)-cyclohexylamin 4C 59 (syn,syn)-2-(Dimethylamino-(2-nitrophenyl)-methyl)-cyclohexylamin 4A/B 60 (anti,anti)-2-(Dimethylamino-(2-nitrophenyl)-methyl)-cyclohexylamin 4C The compounds prepared by way of example according to AAV 1-6 are shown in Table 1. The determination of the stereochemistry was carried out by means of 1 H and 13 C NMR investigations, in particular by comparison of the chemical shifts of the C atoms C-NR 3 R 4 , CR 1 and CA in the 13 C-NMR spectrum of the compounds according to the invention with one another and with the displacements of the corresponding C atoms in the 13 C-NMR spectrum of (anti, anti) -1-hydroxy-2- (pyrrolidine-phenyl-methyl) -cyclohexane and (syn, anti) -1-hydroxy-2- (pyrrolidin-phenyl-methyl) -cyclohexane. <u> Table 1 </ u> Example no. connection Manufacturing process (AAV) 1 (Syn, syn) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] benzamide hydrochloride 4A / B + 5 + 6 1a (Syn, syn) -2- (dimethylamino-3-ylmethyl) cyclohexylamine 4A / B 2 (Syn, syn) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] -2-fluorobenzamide hydrochloride 4A / B + 5 + 6 3 (Syn, syn) -2-chloro-N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] benzamide hydrochloride 4A / B + 5 + 6 4 (Syn, syn) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] -2-methylbenzamide hydrochloride 4A / B + 5 + 6 5 (Anti, anti) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] benzamide hydrochloride 4C + 5 + 6 5a (Anti, anti) -2- (dimethylamino-3-ylmethyl) cyclohexylamine 4C 6 (Anti, anti) -N- [2- (dimethylamino-3-ylmethyl) cyclo-hexyl] -2-fluorobenzamide hydrochloride 4C + 5 + 6 7 (Anti, anti) -2-chloro-N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] benzamide hydrochloride 4C + 5 + 6 8th (Anti, anti) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] -2-methylbenzamide hydrochloride 4C + 5 + 6 9 (Syn, syn) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] acetamide hydrochloride 4A / B + 5 + 6 10 (Anti, anti) -N- [2- (dimethylamino-3-ylmethyl) cyclohexyl] acetamide hydrochloride 4C + 5 + 6 11 (Syn, syn) -N- [2- (dimethylaminophenylmethyl) cyclohexyl] -2-fluorobenzamide hydrochloride 4A / B + 5 + 6 11a (Syn, syn) -2- (dimethylaminophenylmethyl) cyclohexylamine 4A / B 12 (Syn, syn) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -acetamide hydrochloride 4A / B + 5 + 6 13 (Syn, syn) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -benzamide hydrochloride 4A / B + 5 + 6 14 (Syn, syn) -2-chloro-N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -benzamide hydrochloride 4A / B + 5 + 6 15 (Syn, syn) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -2-methyl-benzamide hydrochloride 4A / B + 5 + 6 16 (Anti, anti) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -acetamide hydrochloride 4C + 5 + 6 16a -2- (anti, anti) (dimethylamino-phenyl-methyl) -cyclohexylamine 4C 17 (Anti, anti) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -benzamide hydrochloride 4C + 5 + 6 18 (Anti, anti) -N- [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -2-methyl-benzamide hydrochloride 4C + 5 + 6 19 (Syn, syn) -2-chloro-N- {2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexyl} -benzamide hydrochloride 4A / B + 5 + 6 19a (Syn, syn) -2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexylamine 4A / B 20 (Anti, anti) -2-chloro-N- {2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexyl} -benzamide hydrochloride 4C + 5 + 6 20a (Anti, anti) -2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexylamine 4C 21 (Syn, syn) -N- {2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexyl} -2-fluoro-benzamide hydrochloride 4A / B + 5 + 6 22 (Anti, anti) -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -benzamide hydrochloride 4C + 5 + 6 22a (Anti, anti) -2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexylamine 4C 23 -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} (anti, anti) -2-fluoro-benzamide hydrochloride 4C + 5 + 6 24 (Anti, anti) -2-chloro-N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -benzamide hydrochloride 4C + 5 + 6 25 -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} (anti, anti) -2-methyl-benzamide hydrochloride 4C + 5 + 6 26 (Syn, syn) -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -acetamide hydrochloride 4A / B + 5 + 6 26a (Syn, syn) -N-2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexylamine 4A / B 27 (Anti, anti) -N- {2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexyl} -acetamide hydrochloride 4C + 5 + 6 28 -2- (syn, anti) (dimethylamino-phenyl-methyl) -cyclohexylamine 1 + 2 29 -N- (syn, anti) [2- (dimethylamino-phenyl-methyl) -cyclohexyl] -benzamide 1 30 (Anti, anti) -N- {2- [dimethylamino- (2-methoxy-phenyl) -methyl] -cyclohexyl} -benzamide 4C + 5 30a (Anti, anti) -2- [dimethylamino- (2-methoxy-phenyl) -methyl] -cyclohexylamine 4C 31 (Anti, anti) -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -benzamide 4C + 5 33 (Anti, anti) -N- {2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexyl} -benzamide 4C + 5 35 (Anti, anti) -N- {2- [dimethylamino- (2-methoxy-phenyl) -methyl] -cyclohexyl} -acetamide 4C + 5 36 (Anti, anti) - {2 - [(2-chloro-phenyl) -dimethylamino-methyl] -cyclohexyl} -acetamide 4C + 5 37 (Anti, anti) -N- {2- [dimethylamino- (2-nitro-phenyl) -methyl] -cyclohexyl} -acetamide 4C + 5 38 (Syn, syn) -2- (dimethylamino-phenyl-methyl) -cyclohexylamine 4A / B 40 (Anti, anti) -2-chloro-N- (3-dimethylamino-1-ethyl-2-methyl-3-phenyl-propyl) -benzamide 4C + 5 40a (anti, anti) -3-dimethylamino-1-ethyl-2-methyl-3-phenylpropylamine 4C 41 (Syn, anti) -2- (dimethylamino-phenyl-methyl) -cyclohexyl-N- (n-propyl) -amine 1 42 (Syn, anti) -2- (morpholin-4-yl-phenyl-methyl) -cyclohexyl-N- (n-propyl) -amine 1 43 (Syn, anti) -2, N, N-trimethyl-1,3-diphenyl-N'-propyl-propane-1,3-diamine 1 44 (Syn, anti) -2- (dimethylamino-phenyl-methyl) -cyclohexyl-N-benzyl-amine 1 45 (Syn, anti) -2- (morpholin-4-yl-phenyl-methyl) -cyclohexyl-N-benzyl-amine 1 46 (Syn, anti) -2, N, N-trimethyl-1,3-diphenyl-N'-benzyl-propane-1,3-diamine 1 47 -2- (syn, anti) (dimethylamino-phenyl-methyl) -cyclohexylamine 1 + 2; 3 48 (Syn, anti) -2- (morpholin-4-yl-phenyl-methyl) -cyclohexylamine 1 + 2 49 (Syn, anti) -2, N, N-trimethyl-1,3-diphenyl-propane-1,3-diamine 1 + 2 50 (Syn, anti) -2 - [(2-chlorophenyl) -dimethylamino-methyl] -cyclohexylamine 3 51 (Anti, anti) -2 - [(2-chlorophenyl) -dimethylamino-methyl] -cyclohexylamine 4C 52 (Syn, syn) -2- (dimethylamino-phenyl-methyl) -cyclohexylamine 4A / B 53 -2- (anti, anti) (dimethylamino-phenyl-methyl) -cyclohexylamine 4C 54 (Syn, syn) -2 - [(2-Chtorphenyl) -dimethylamino-methyl] -cyclohexylamine 4A / B 55 (Syn, syn) -2- (dimethylamino-pyridin-3-yl-methyl) -cyclohexylamine 4A / B 56 (Anti, anti) -2- (dimethylamino-pyridin-3-yl-methyl) -cyclohexylamine 4C 57 (Syn, syn) -2- (dimethylamino- (2-methoxyphenyl) -methyl) -cyclohexylamine 4A / B 58 (Ant, anti) -2- (dimethylamino- (2-methoxyphenyl) -methyl) -cyclohexylamine 4C 59 (Syn, syn) -2- (dimethylamino- (2-nitrophenyl) -methyl) -cyclohexylamine 4A / B 60 (Anti, anti) -2- (dimethylamino- (2-nitrophenyl) -methyl) -cyclohexylamine 4C

Spektroskopische DatenSpectroscopic data

Die spektroskopischen Daten einiger ausgewählter Beispiels-Verbindungen sind in den Tabellen 2 bis 5 wiedergegeben. Tabelle 2 Beispiels-Nr. 1H NMR (CDCl3) / TMS) δ [ppm], J [Hz] 13C NMR (CDCl3) / TMS) δ [ppm] IR ν [cm-1] 44 0.74 - 0.83 (m, 1 H, ]-(CH2)4-[ ), 1.07 - 1.28 (m, 3 H, ]-(CH2)4-[), 1.57 - 1.70 (m, 3 H, ]-(CH2)4-[), 1.94 - 2.09 (m, 1 H, CHCHCH), 2.12 (6 H, N(CH3)2), 2.14 - 2.20 (m, 1 H, ]-(CH2)4-[), 2.29 - 2.36 (m, 1 H, CHCHCH), 3.65 (d, 1 H, J = 12.8, PhCH), AB-System (δA = 3.65, δB = 3.95, J = 12.8, CH2Ph), 7.11 - 7.40 (m, 10 H. Ar-H). 24.41, 25.42, 27.49, 31.68 (t, ]-(CH2)4-[), 41.42 (d, CHCHCHPh), 42.23 (q, N(CH3)2), 50.75 (t, CH2Ph), 60.44 (d, CHCHCHPh), 73.79 (d, CHPh), 126.50, 126.52, 127.31, 128.01, 128.17, 129.33 (d, CH), 136.36, 141.00 (s, C). 3444, 1635, 1557, 1452, 1028, 744, 698. 45 0.62 - 2.36 (m, 14 H, ]-(CH2)4-[, CHCHCHPh, CHCHCH-Ph, ]-CH2-N-CH2[), 3.36 - 3.97 (m, 7 H, CH2Ph, ]-CH2-O-CH2-[, CHPh), 7.11 - 7.37 (m, 10 H, Ar-H). 25.04, 26.31, 29.49, 33.96 (t, ]-(CH2)4[), 48.13 (d, CHCHCHPh), 51.54, 52.18 (t, ]-CH2-N-CH2-[, CH2Ph), 61.83 (d, CHCHCHPh), 67.32 (t, -CH2-OCH2-), 67.40 (d, CHPh), 127.25, 128.57, 128.63, 128.71, 128.86 (d, CH), 141.34, 143.13 (s, C). 3446, 2924, 2852, 1627, 1451, 1383, 1251, 1106, 1070, 700. 46 0.53 (d, 3 H, J = 6.8 Hz, CHCH 3), 2.19 (s, 6 H, N(CH3)2), 2.46 - 2.65 (m, 1 H, CHCH3), 3.23 (d, 1 H, J = 9.4, PhCH), AB-System (δA = 3.57, δB= 3.71, J = 13.1, CH2Ph), 3.93 (d, 1H, J = 6.3, PhCH), 7.13 - 7.52 (15 H, Ar-H). 13.58 (t, CH3CH), 39.37 (d, CH3CH), 42.05 (q, N(CH3)2), 52.19 (t, CH2Ph), 64.80, 73.07 (d, PhCH), 127.18, 127.97, 128.36, 128.70, 128.77, 128.98. 129.10, 129.93 (d, CH), 136.48, 141.56, 142.63 (s, C). 3025, 2940, 2791, 1605, 1476, 1444. 1365, 1073, 1028, 754. Tabelle 3 Beispiels-Nr. 1H NMR (CDCl3) /TMS) δ [ppm], J [Hz] 13C NMR (CDCl3) / TMS) δ [ppm] IR ν (cm-1) 47 0.70 - 1.89 (m, 9 H, ]-(CH2)4-[, CHCHCHPh), 2.16 (s, 6 H. N(CH3)2), 2.43- 2.53 (m, 1 H, CHCHCHPh), 3.40 (d, 1 H, J = 10.9, CHPh), 7.09 -7.42 (m, 5 H, Ar-H). 24.90. 25.13.30.23.31.83 (t, ]-(CH2)4-[), 38.17 (q, N(CH3)2), 45.13 (d, CHCHCHPh), 57.94 (d, CHCHCHPh), 76.65 (d, CHPh), 127.26, 128.03, 129.83 (d, CH), 137.29 (s, C). 3339, 2955, 2852, 2868.1557.1458. 1452, 1381. 48 0.40 - 2.60 (m, 13 H,]-(CH2)4-[,CHCHCHPh, ]-CH2-N-CH2-[ ), 3.16 - 3.96 (m, 5 H, ]-CH2-O-CH2-[, CHCHCHPh), 4.19 (d, 1 H, J = 10.0, CHPh), 7.21 - 7.56 (m, 5 H, Ar-H). 25.41. 26.11, 27.26, 37.45 (t, ]-(CH2)4-[), 44.34 (d, CHCHCH), 51.56 (t, ]-CH2-N-CH2-[), 54.22 (d, CHCHCHPh), 67.40 (t, ]-CH2-O-CH2-[), 67.71 (d, CHPh), 126.83, 127.41, 128.15, 128.59, 129.85 (d, CH), 137.56 (s, C). 3440, 2921, 2852, 1652, 1456, 1448, 1384, 1113, 1031, 703. 49 0.48 (d, 3 H, J = 6.8, CHCH 3), 2.15 (s, 6 H, N(CH3)2), 2.65-2.41 (m, 1 H, CHCH3), 3.13 (d, 1 H, J = 9.4, N(CH3)2CH), 4.14 (d. 1 H, J = 6.0, CHNH2), 7.09 - 7.42 (m, 10 H, Ar-H). 13.00 (q, CHCH3), 40.75 (d, CHCH3), 42.16 (q, N(CH3)2), 57.84 (d, N(CH3)2CH), 72.94 (d, NH2CH), 127.09, 127.27, 128.03, 128.13, 128.37, 129.89 (d, CH), 136.54, 145.08 (s, C). 2950, 2929, 2858, 1729, 1452, 1383, 1185, 1029, 50 0.60 - 2.06 (m, 9 H, ]-(CH2)4-[, CHCHCHPh), 2.50 (s, 6 H, N(CH3)2), 3.10 - 3.19 (m. 2 H, CHPh, CHCHCHPh), 7.08 - 7.51 (m, 4 H, Ar-H). 25.01,25.69,30.01,31.65 (t, ]-(CH2)4-[), 38.34 (q, N(CH3)2), 43.47 (d, CHCHCHPh), 69.72 (d, CHPh), 77.98 (d, CHCHCHPh), 127.22, 128.83, 128.95.129.35 (d, CH), 133.27, 135.66 (s, C). 3430, 2929, 1635, 1438,1062, 750. 51 0.60 - 2.06 (m, 9 H, ]-(CH2)4-[, CHCHCHPh), 2.50 (s, 6 H, N(CH3)2), 3.10 - 3.19 (m, 2 H, CHPh, CHCHCHPh), 7.08 - 7.51 (m, 4 H, Ar-H). 25.01, 25.69, 30.01, 31.65 (t, ]-(CH2)4-[), 38.34 (q, N(CH3)2), 43.47 (d, CHCHCHPh), 69.72 (d, CHPh), 77.98 (d, CHCHCHPh), 127.22, 128.83, 128.95, 129.35 (d, CH), 133.27, 135.66 (s, C). Tabelle 4 Beispiels-Nr. 1H NMR (CDCl3) / TMS) δ [ppm], J [Hz] 13C NMR (CDCl3) / TMS) δ [ppm] IR ν [cm-1] MS (70 eV) m/z[%] 52 0.96 - 2.13 (m, 8 H, ]-(CH2)4-[, CHCHCHPh), 2.17 (s. 6 H, N(CH3)2), 2.25 - 2.60 (m, 1 H, CHCHCHPh), 3.74 - 4.06 (m, 2 H, CHCHCHPh, CHPh), 7.09 - 7.53 (m, 5 H, Ar-H). 21.86, 24.22,27.45, 32.40 37 (t, ]-(CH2)4-[), 37.96 (d, CHCHCHPh), 41.25 (q, N(CH3)2), 68.97 CHCHCHPh), 71.90 (d, CHPh), 127.85, 128.26, 130.24 (d, CH), 136.86 (s, C). 3405, 2929, 2857, 2782, 1450.1384. 1068, 975, 752, 703. 232 [M+] (13), 134 (100), 118 (5), 91 (9), 77 (3). 54 0.96 -1.88 (m, 8 H, ]-(CH2)4-[) 2.23 (s, 6 H, N(CH3)2), 2.31 - 2.56 (m, 1 H, CHCHCH), 3.94 - 4.03 (m, 1 H, CHCHCHPh), 4.90 (d, 1 H, J = 11.6, CHPh), 7.20 - 7.48 (m, 4 H, Ar-H). 21.76, 24.63, 27.70, 32.37 (t, ]-(CH2)4-[), 38.50 (d, CHCHCHPh), 41.49 (q, N(CH3)2), 62.27 (CHCHCHPh), 72.56 (d, CHPh), 126.42, 128.88, 130.41, 130.56 (d, CH), 132.68, 136.42 (s, C). 3434, 2929, 2859, 2782, 1643, 1463, 1062, 1035, 975, 754. 267 [M+] (53), 167 (100), 130 (7). 55 0.89 - 1.87 (m, 8 H, ]-(CH2)4-[) 2.13 (s, 6 H, N(CH3)2), 2.42 - 2.54 (m, 1 H, CHCHCH), 3.71 - 4.02 (m, 2 H, CHCHCHPh, CHPh), 7.29 - 7.49 (m, 2 H, Ar-H), 8.41 - 8.56 (m, 2 H, Ar-H). 22.10, 23.72, 27.12, 32.33 (t, ]-(CH2)4-[), 38.10 (d, CHCHCHPh), 41.16 (q, N(CH3)2), 66.79 (CHCHCHPh), 71.13 (d, CHPh), 123.43 (d, CH), 128.90 (s, C), 137.13, 149.33, 151.32 (d, CH). 3417, 2927, 2857, 1646, 1062, 1029, 977. 235 [M++ 1], 217 (2), 164 (5),135 (100),119 (4) 92 (2). 57 0.95 - 1.94 (m, 8 H, ]-(CH2)4- D, 2.15 (s, 6 H, N(CH3)2), 2.48 - 2.56 (m, 1 H, CHCHCH), 3.73 - 4.00 (m, 2 H, CHCHCHPh, CHPh), 3.83 (s, 3 H, OMe), 6.94 - 7.01 (m, 2 H, Ar-H). 7.12 (d, 1 H, J = 7.5, Ar-H), 7.28 - 7.33 (m. 1 H, Ar-H). 21.43,24.92,27.97.32.32 (t, ]-(CH2)4[), 38.02 (d, CHCHCHPh), 41.42 (q, N(CH3)2),55.87 (CHCHCHPh), 73.01 (d, CHPh), 111.30, 120.11, 122.38 (s, C), 128.64. 129.65 43 (d, CH), 158.98 (s, C). 3426,2927, 2857,2784, 1068,975, 752, 703. 263[M++ 1](3), 218 (2), 164 (100),148 (12), 121 (7). 91 (8). 59 0.81 - 1.91 (m, 8 H, )-(CH2)4-[, CHCHCH), 1.98 (s, 6 H, N(CH3)2), 2.20 - 2.46 (m, 2 H, CHCHCH), 3.51 - 3.69 (m, 1 H, CHCHCHPh), 4.73 (d, 1 H, J = 11.3, CHPh), 7.29 - 7.41 (m, 2 H, Ar-H), 7.51 - 7.59 (m, 1 H, Ar-H), 7.69 (d, 1 H, J = 8.0). 22.70, 23.41, 25.92, 32.55 (t, ]-(CH2)4-[), 39.03 (d, CHCHCHPh), 40.99 (q, N(CH3)2), 60.88 CHCHCHPh), 70.51 (d, CHPh), 124.42 (d, CH), 127.92 (s, C), 128.37, 130.27, 131.56 (d, CH), 152.76 (s, C). 3417, 2931, 2859, 1527, 1455, 1068, 977. 277 [M+] (12), 261 (3), 179 (100), 132 (37), 91 (5). Tabelle 5 Beispiels-Nr. 1H NMR (CDCl3) / TMS) δ [ppm], J [Hz] 13C NMR (CDCl3) / TMS) δ [ppm] IR ν [cm-1] MS (70 eV) m/z [%] 53 0.53-2.50 (m, 9 H, ]-(CH2)4-[, CHCHCH), 2.17 (s, 6 H, N(CH3)2), 3.41- 3.76 (m, 2 H, CHCHCHPh, CHPh), 7.08 - 7.44 (m, 5 H, Ar-H). 25.03, 26.20, 29.29, 35.37 (t, ]-(CH2)4-[), 41.32 (d, CHCHCHPh), 42.75 (q, N(CH3)2), 76.60 (CHCHCHPh), 78.00 (d, CHPh), 127.79, 128.17 (d, CH), 137.45 (s, C). 3421, 2929, 2857, 2782, 1450, 1384, 1062, 1043, 1033, 975. 232 [M+] (19), 134 (100), 91 (9), 77(3). 56 0.57 - 2.07 (m, 9 H, ]-(CH2)4-[, CHCHCH), 2.14 (s. 6 H, N(CH3)2), 3.44 - 3.63 (m. 2 H, CHCHCHPh, CHPh), 7.29 - 7.56 (m, 2 H, Ar-H), 8.35 - 8.54 (m, 2 H, Ar-H). 24.83, 26.03, 29.22, 35.19 (t, ]-(CH2)4-[), 41.22 (q, N(CH3)2), 42.47 (d, CHCHCHPh), 74.10 (CHCHCHPh), 77.77 (d, CHPh), 123.37(d, CH), 129.63 (s, C), 136.83. 149.32, 151.24 (d, CH). 3421, 2929, 2857, 1445, 1384, 1070, 1043, 977. 234 [M+], 164 (5), 135 (100), 91 (5). 58 0.61 - 2.52 (m, 9 H, ]-(CH2)4-[, CHCHCH), 2.17 (s, 6 H, N(CH3)2), 3.48 - 3.69 (m, 1 H, CHCHCHPh), 3.83 (s, 3 H, OCH3), 4.40 (d, 1 H, J = 11.1, CHPh), 6.92 - 7.30 (m, 4 H, Ar-H). 25.08, 26.22, 28.87, 35.38 (t, ]-(CH2)4-[), 41.59 (d, CHCHCHPh), 42.93 (q, N(CH3)2), 55.76 (q, OCH3), 65.42 (CHCHCHPh), 77.98 (d, CHPh), 110.70, 120.40 (d, CH), 122.75 (s, C),127.99, 130.82 (d, CH), 159.16 (s, C). 3423, 2934, 2857, 2784, 1068, 975, 752, 703. 262 [M+] (3), 164 (100), 148 (20), 121 (10), 91 (6). 60 0.92 - 2.49 (m, 9 H, ]-(CH2)4-[, CHCHCH), 2.07 (s, 6 H, N(CH3)2), 3.63 - 3.73 (m, 1 H, CHCHCHPh), 4.42 (d, 1 H, J = 10.6 Hz, CHPh), 7.33 - 7.81 (m, 4 H, Ar-H). 24.75, 26.03, 28.42, 35.11 (t, ]-(CH2)4-[), 41.40 (q, N(CH3)2), 43.02 (d, CHCHCHPh), 67.78 (CHCHCHPh), 77.54 (d, CHPh), 124.41, 128.54, 129.37 (s, C), 130.54, 131.81 (d, CH), 152.45 (s, C). 3415, 2936, 2864, 1523, 1455, 1068, 977. 277 [M+] (20), 179 (100), 132 (37), 91 (30). The spectroscopic data of some selected example compounds are given in Tables 2 to 5. <u> Table 2 </ u> Example no. 1 H NMR (CDCl 3) / TMS) δ [ppm], J [Hz] 13 C NMR (CDCl 3) / TMS) δ [ppm] IR ν [cm -1 ] 44 0.74 - 0.83 (m, 1 H,] - (CH 2 ) 4 - [), 1.07 - 1.28 (m, 3 H,] - (CH 2 ) 4 - [, 1.57 - 1.70 (m, 3 H,] - (CH 2 ) 4 - [), 1.94 - 2.09 (m, 1 H, CHC H CH), 2.12 (6 H, N (CH 3 ) 2 ), 2.14 - 2.20 (m, 1 H,] - (CH 2 ) 4 - [), 2.29 - 2.36 (m, 1 H, C H CHCH), 3.65 (d, 1 H, J = 12.8, PhCH), AB system (δ A = 3.65, δ B = 3.95, J = 12.8, CH 2 Ph), 7.11-7.40 (m, 10H Ar-H). 24.41, 25.42, 27.49, 31.68 (t,] - (CH 2 ) 4 - [, 41.42 (d, CHCHCHPh), 42.23 (q, N (CH 3 ) 2 ], 50.75 (t, CH 2 Ph), 60.44 (d, CHCHCHPh), 73.79 (d, CHPh), 126.50, 126.52, 127.31, 128.01, 128.17, 129.33 (d, CH), 136.36, 141.00 (s, C). 3444, 1635, 1557, 1452, 1028, 744, 698. 45 0.62-2.26 (m, 14 H,] - (CH 2 ) 4 - [, C H CHCHPh, CHC H CH-Ph,] -CH 2 -N-CH 2 [), 3.36 - 3.97 (m, 7 H, CH 2 Ph,] -CH 2 -O-CH 2 - [, CHPh], 7.11-7.37 (m, 10 H, Ar-H). 25.04, 26.31, 29.49, 33.96 (t,] - (CH 2 ) 4 [), 48.13 (d, CHCHCHPh), 51.54, 52.18 (t,] -CH 2 -N-CH 2 - [, CH 2 Ph), 61.83 (d, CHCHCHPh), 67.32 (t, -CH 2 -OCH 2 -), 67.40 (d, CHPh), 127.25, 128.57, 128.63, 128.71, 128.86 (d, CH), 141.34, 143.13 (s, C) , 3446, 2924, 2852, 1627, 1451, 1383, 1251, 1106, 1070, 700. 46 0:53 (d, 3 H, J = 6.8 Hz, CHC H 3), 2.19 (s, 6 H, N (CH 3) 2) 2.46 - 2.65 (m, 1 H, C H CH 3), 3.23 (d , 1 H, J = 9.4, PhCH), AB system (δ A = 3.57, δ B = 3.71, J = 13.1, CH 2 Ph), 3.93 (d, 1H, J = 6.3, PhCH), 7.13-7.52 (15H, Ar-H). 13.58 (t, CH 3 CH), 39.37 (d, CH 3 CH), 42.05 (q, N (CH 3 ) 2 ), 52.19 (t, CH 2 Ph), 64.80, 73.07 (d, PhCH), 127.18, 127.97, 128.36, 128.70, 128.77, 128.98. 129.10, 129.93 (d, CH), 136.48, 141.56, 142.63 (s, C). 3025, 2940, 2791, 1605, 1476, 1444. 1365, 1073, 1028, 754. Example no. 1 H NMR (CDCl 3) / TMS) δ [ppm], J [Hz] 13 C NMR (CDCl 3) / TMS) δ [ppm] IR ν (cm -1 ) 47 0.70-1.89 (m, 9 H,] - (CH 2 ) 4 - [, CHC H CHPh], 2.16 (s, 6H, N (CH 3 ) 2 ), 2.43-2.53 (m, 1H, CHCHCHPh) , 3.40 (d, 1H, J = 10.9, CHPh), 7.09-7.42 (m, 5H, Ar-H). 24.90. 25.13.30.23.31.83 (t,] - (CH 2) 4 - [), 38.17 (q, N (CH 3) 2), 45.13 (d, CHCHCHPh), 57.94 (d, CHCHCHPh), 76.65 (d, CHPh ), 127.26, 128.03, 129.83 (d, CH), 137.29 (s, C). 3339, 2955, 2852, 2868.1557.1458. 1452, 1381. 48 0.40-2.60 (m, 13 H,] - (CH 2 ) 4 - [, CHC H CHPh,] -CH 2 -N-CH 2 - [), 3.16 - 3.96 (m, 5 H,] -CH 2 - O-CH 2 - [, C H CHCHPh], 4.19 (d, 1 H, J = 10.0, CHPh), 7.21-7.56 (m, 5 H, Ar-H). 25.41. 26.11, 27.26, 37.45 (t,] - (CH 2 ) 4 - [, 44.34 (d, CHCHCH), 51.56 (t,] -CH 2 -N-CH 2 - [), 54.22 (d, CHCHCHPh), 67.40 (t,] -CH 2 -O-CH 2 - [, 67.71 (d, CHPh), 126.83, 127.41, 128.15, 128.59, 129.85 (d, CH), 137.56 (s, C). 3440, 2921, 2852, 1652, 1456, 1448, 1384, 1113, 1031, 703. 49 0:48 (d, 3 H, J = 6.8, CHC H 3), 2.15 (s, 6 H, N (CH 3) 2), 2.65-2.41 (m, 1 H, C H CH 3), 3.13 (d, 1 H, J = 9.4, N (CH 3 ) 2 C H ), 4.14 (i.e., 1 H, J = 6.0, CHNH 2 ), 7.09-7.42 (m, 10 H, Ar-H). 13:00 (q, CHCH 3), 40.75 (d, CHCH 3), 42.16 (q, N (CH 3) 2), 57.84 (d, N (CH 3) 2 CH), 72.94 (d, NH 2 CH), 127.09, 127.27, 128.03, 128.13, 128.37, 129.89 (d, CH), 136.54, 145.08 (s, C). 2950, 2929, 2858, 1729, 1452, 1383, 1185, 1029, 50 0.60 - 2.06 (m, 9 H,] - (CH 2 ) 4 - [, CHC H CHPh], 2.50 (s, 6 H, N (CH 3 ) 2 ), 3.10 - 3.19 (m, 2 H, CHPh, C H CHCHPh), 7:08 to 7:51 (m, 4 H Ar-H). 25.01,25.69,30.01,31.65 (t,] - (CH 2) 4 - [), 38.34 (q, N (CH 3) 2), 43.47 (d, CHCHCHPh), 69.72 (d, CHPh), 77.98 (d , CHCHCHPh), 127.22, 128.83, 128.95.129.35 (d, CH), 133.27, 135.66 (s, C). 3430, 2929, 1635, 1438, 1062, 750. 51 0.60-2.06 (m, 9 H,] - (CH 2 ) 4 - [, CHC H CHPh], 2.50 (s, 6 H, N (CH 3 ) 2 ), 3.10-3.19 (m, 2 H, CHPh, CHCHCHPh), 7.08-7.51 (m, 4H, Ar-H). 25.01, 25.69, 30.01, 31.65 (t,] - (CH 2) 4 - [), 38.34 (q, N (CH 3) 2), 43.47 (d, CHCHCHPh), 69.72 (d, CHPh), 77.98 (d , CHCHCHPh), 127.22, 128.83, 128.95, 129.35 (d, CH), 133.27, 135.66 (s, C). Example no. 1 H NMR (CDCl 3) / TMS) δ [ppm], J [Hz] 13 C NMR (CDCl 3) / TMS) δ [ppm] IR ν [cm -1 ] MS (70 eV) m / z [%] 52 0.96 - 2.13 (m, 8 H,] - (CH 2 ) 4 - [, CHC H CHPh], 2.17 (see 6 H, N (CH 3 ) 2 ), 2.25 - 2.60 (m, 1 H, CHC H CHPh), 3.74-4.06 (m, 2H, CHCHCHPh, CHPh), 7.09-7.53 (m, 5H, Ar-H). 21.86, 24.22, 27.45, 32.40 37 (t,] - (CH 2 ) 4 - [, 37.96 (d, CHCHCHPh), 41.25 (q, N (CH 3 ) 2 ), 68.97 CHCHCHPh), 71.90 (d, CHPh ), 127.85, 128.26, 130.24 (d, CH), 136.86 (s, C). 3405, 2929, 2857, 2782, 1450.1384. 1068, 975, 752, 703. 232 [M + ] (13), 134 (100), 118 (5), 91 (9), 77 (3). 54 0.96 -1.88 (m, 8 H,] - (CH 2 ) 4 - [) 2.23 (s, 6 H, N (CH 3 ) 2 ), 2.31 - 2.56 (m, 1 H, CHC H CH), 3.94 - 4:03 (m, 1 H, C H CHCHPh), 4.90 (d, 1 H, J = 11.6, C H Ph), 7:20 to 7:48 (m, 4 H, Ar-H). 21.76, 24.63, 27.70, 32.37 (t,] - (CH 2) 4 - [), 38.50 (d, CHCHCHPh), 41.49 (q, N (CH 3) 2), 62.27 (CHCHCHPh), 72.56 (d, CHPh ), 126.42, 128.88, 130.41, 130.56 (d, CH), 132.68, 136.42 (s, C). 3434, 2929, 2859, 2782, 1643, 1463, 1062, 1035, 975, 754. 267 [M + ] (53), 167 (100), 130 (7). 55 0.89- 1.87 (m, 8H,] - (CH 2 ) 4 - [) 2.13 (s, 6H, N (CH 3 ) 2 ), 2.42 - 2.54 (m, 1H, CHCHCH), 3.71 - 4.02 ( m, 2H, CHCHCHPh, CHPh), 7.29-7.49 (m, 2H, Ar-H), 8.41-8.56 (m, 2H, Ar-H). 10.22, 23.72, 27.12, 32.33 (t,] - (CH 2) 4 - [), 38.10 (d, CHCHCHPh), 41.16 (q, N (CH 3) 2), 66.79 (CHCHCHPh), 71.13 (d, CHPh ), 123.43 (d, CH), 128.90 (s, C), 137.13, 149.33, 151.32 (d, CH). 3417, 2927, 2857, 1646, 1062, 1029, 977. 235 [M + + 1], 217 (2), 164 (5), 135 (100), 119 (4) 92 (2). 57 0.95 - 1.94 (m, 8 H,] - (CH 2) 4 - D, 2.15 (s, 6 H, N (CH 3) 2), 2:48 to 2:56 (m, 1H, CHCHCH), 3.73 - 4.00 ( m, 2 C H CHCHPh, CHPh), 3.83 (s, 3 H, OMe), 6.94 H, - 7:01 (m, 2 H, Ar-H) 7.12 (d, 1 H, J = 7.5, Ar-H. ), 7.28 - 7.33 (m, 1H, Ar-H). 21.43,24.92,27.97.32.32 (t,] - (CH 2) 4 [), 38.02 (d, CHCHCHPh), 41.42 (q, N (CH 3) 2), 55.87 (CHCHCHPh), 73.01 (d, CHPh) , 111.30, 120.11, 122.38 (s, C), 128.64. 129.65 43 (d, CH), 158.98 (s, C). 3426,2927, 2857,2784, 1068,975, 752, 703. 263 [M + + 1] (3), 218 (2), 164 (100), 148 (12), 121 (7). 91 (8). 59 0.81 - 1.91 (m, 8 H,) - (CH 2) 4 - [CHC H CH), 1.98 (s, 6 H, N (CH 3) 2), 2:20 to 2:46 (m, 2 H, CH₂ CH ₂CH₂) 3.51 - 3.69 (m, 1 H, C H CHCHPh), 4.73 (d, 1 H, J = 11.3, C H Ph), 7:29 to 7:41 (m, 2, Ar-H,), 7:51 to 7:59 (m, 1 H, Ar-H), 7.69 (d, 1H, J = 8.0). 22.70, 23:41, 25.92, 32.55 (t,] - (CH 2) 4 - [), 39.03 (d, CHCHCHPh), 40.99 (q, N (CH 3) 2), 60.88 CHCHCHPh), 70.51 (d, CHPh) , 124.42 (d, CH), 127.92 (s, C), 128.37, 130.27, 131.56 (d, CH), 152.76 (s, C). 3417, 2931, 2859, 1527, 1455, 1068, 977. 277 [M + ] (12), 261 (3), 179 (100), 132 (37), 91 (5). Example no. 1 H NMR (CDCl 3) / TMS) δ [ppm], J [Hz] 13 C NMR (CDCl 3) / TMS) δ [ppm] IR ν [cm -1 ] MS (70 eV) m / z [%] 53 0:53 to 2:50 (m, 9 H,] - (CH 2) 4 - [, CHCHCH), 2.17 (s, 6 H, N (CH 3) 2), 3.41- 3.76 (m, 2 H, C H CHCHPh, CHPh), 7.08-7.44 (m, 5H, Ar-H). 25.03, 26.20, 29.29, 35.37 (t,] - (CH 2) 4 - [), 41.32 (d, CHCHCHPh), 42.75 (q, N (CH 3) 2), 76.60 (CHCHCHPh), 78.00 (d, CHPh ), 127.79, 128.17 (d, CH), 137.45 (s, C). 3421, 2929, 2857, 2782, 1450, 1384, 1062, 1043, 1033, 975. 232 [M + ] (19), 134 (100), 91 (9), 77 (3). 56 0.57 - 2.07 (m, 9 H,] - (CH 2 ) 4 - [, CHC H CH], 2.14 (see 6 H, N (CH 3 ) 2 ), 3.44 - 3.63 (m 2 H, C H CHCHPh, CHPh), 7.29-7.56 (m, 2H, Ar-H), 8.35-8.54 (m, 2H, Ar-H). 24.83, 26.03, 29.22, 35.19 (t,] - (CH 2) 4 - [), 41.22 (q, N (CH 3) 2), 42.47 (d, CHCHCHPh), 74.10 (CHCHCHPh), 77.77 (d, CHPh ), 123.37 (d, CH), 129.63 (s, C), 136.83. 149.32, 151.24 (d, CH). 3421, 2929, 2857, 1445, 1384, 1070, 1043, 977. 234 [M + ], 164 (5), 135 (100), 91 (5). 58 0.61 - 2.52 (m, 9 H,] - (CH 2 ) 4 - [, CHC H CH], 2.17 (s, 6 H, N (CH 3 ) 2 ), 3.48 - 3.69 (m, 1 H, C H CHCHPh), 3.83 (s, 3 H, OCH 3), 4:40 (d, 1 H, J = 11.1, CHPh), 6.92 - 7.30 (m, 4 H, Ar-H). 25.08, 26.22, 28.87, 35.38 (t,] - (CH 2 ) 4 - [, 41.59 (d, CHCHCHPh), 42.93 (q, N (CH 3 ) 2 ], 55.76 (q, OCH 3 ), 65.42 ( CHCHCHPh), 77.98 (d, CHPh), 110.70, 120.40 (d, CH), 122.75 (s, C), 127.99, 130.82 (d, CH), 159.16 (s, C). 3423, 2934, 2857, 2784, 1068, 975, 752, 703. 262 [M + ] (3), 164 (100), 148 (20), 121 (10), 91 (6). 60 0.92 - 2:49 (m, 9 H,] - (CH 2) 4 - [, CHCHCH), 2:07 (s, 6 H, N (CH 3) 2), 3.63 - 3.73 (m, 1 H, CHCHCHPh), 4:42 (d, 1H, J = 10.6Hz, CHPh), 7.33-7.81 (m, 4H, Ar-H). 24.75, 26.03, 28.42, 35.11 (t,] - (CH 2) 4 - [), 41.40 (q, N (CH 3) 2), 43.02 (d, CHCHCHPh), 67.78 (CHCHCHPh), 77.54 (d, CHPh ), 124.41, 128.54, 129.37 (s, C), 130.54, 131.81 (d, CH), 152.45 (s, C). 3415, 2936, 2864, 1523, 1455, 1068, 977. 277 [M + ] (20), 179 (100), 132 (37), 91 (30).

Pharmakologische UntersuchungenPharmacological investigations Analgesieprüfung im Writhing-Test an der MausAnalgesia test in writhing test on the mouse

Die Untersuchung auf analgetische Wirksamkeit wurde im Phenylchinoninduzierten Writhing an der Maus (modifiziert nach I.C. Hendershot und J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240) durchgeführt. Dazu wurden männliche NMRI-Mäuse im Gewicht von 25 bis 30 g verwendet. Gruppen von 10 Tieren pro Substanzdosis erhielten 10 Minuten nach intravenöser Gabe der Prüfsubstanzen 0,3 ml/Maus einer 0,02%igen wäßrigen Lösung von Phenylchinon (Phenylbenzochinon, Fa. Sigma, Deisenhofen; Herstellung der Lösung unter Zusatz von 5 % Ethanol und Aufbewahrung im Wasserbad bei 45°C) intraperitoneal appliziert. Die Tiere wurden einzeln in Beobachtungskäfige gesetzt. Mittels eines Drucktastenzähler wurde die Anzahl der schmerzinduzierten Streckbewegungen (sogenannte Writhingreaktionen = Durchdrücken des Körpers mit Abstrecken der Hinterextremitäten) 5 bis 20 Minuten nach der Phenylchinon-Gabe ausgezählt. Als Kontrolle wurden Tiere mitgeführt, die nur physiologische Kochsalzlösung erhielten. Alle Substanzen wurden in der Standarddosierung von 10 mg/kg getestet. Die prozentuale Hemmung (%Hemmung) der Writhingreaktion durch eine Substanz wurde nach folgender Formel berechnet: % Hemmung = 100 - Writhingreaktionen der behandelten Tiere Writhingreaktionen der Kontrolltiere * 100

Figure imgb0020
The assay for analgesic activity was carried out in phenyl-quinone-induced writhing in the mouse (modified according to IC Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240). For this purpose, male NMRI mice weighing 25 to 30 g were used. Ten minutes after intravenous administration of the test substances, groups of 10 animals per substance dose received 0.3 ml / mouse of a 0.02% strength aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen, preparation of the solution with the addition of 5% ethanol and storage in a water bath at 45 ° C) intraperitoneally. The animals were placed individually in observation cages. By means of a push-button counter, the number of pain-induced stretching movements (so-called writhing reactions) was counted 5 to 20 minutes after the phenylquinone administration. As control animals were carried, which received only physiological saline solution. All substances were tested in the standard dosage of 10 mg / kg. The percentage inhibition (% inhibition) of the writhing reaction by a substance was calculated according to the following formula: % inhibition = 100 - Writhing reactions of the treated animals Writhing reactions of the control animals * 100
Figure imgb0020

Alle untersuchten erfindungsgemäßen Verbindungen zeigten eine ausgeprägte analgetische Wirkung. Die Ergebnisse sind in der nachfolgenden Tabelle 6 zusammengefaßt. Tabelle 6 Beispiels-Nr. %Hemmung der Writhingreaktion (Dosierung in mg/kg intravenös) 1 54 (10) 2 67 (10) 3 85 (10) 4 34 (10) 5 49 (10) 6 62 (10) 7 56 (10) 8 40 (10) 9 75 (10) 10 59 (10) All investigated compounds of the invention showed a pronounced analgesic effect. The results are summarized in Table 6 below. <u> Table 6 </ u> Example no. % Inhibition of the writhing reaction (Dosage in mg / kg intravenously) 1 54 (10) 2 67 (10) 3 85 (10) 4 34 (10) 5 49 (10) 6 62 (10) 7 56 (10) 8th 40 (10) 9 75 (10) 10 59 (10)

Pharmazeutische Formulierung eines erfindungsgemäßen ArzneimittelsPharmaceutical formulation of a medicament according to the invention

1 g des Hydrochlorids von (syn,syn)-2-Chlor-N-[2-(Dimethylaminopyridin-3-ylmethyl)cyclohexyl]-benzamid wurde in 1 l Wasser für Injektionszwecke bei Raumtemperatur gelöst und anschließend durch Zugabe von Natriumchlorid auf isotone Bedingungen eingestellt.1 g of the hydrochloride of (syn, syn) -2-chloro-N- [2- (dimethylaminopyridin-3-ylmethyl) cyclohexyl] benzamide was dissolved in 1 liter of water for injection at room temperature and then by addition of sodium chloride to isotonic conditions set.

Claims (22)

  1. Compound of the general structure (I), or one of its pharmaceutically acceptable salts,
    Figure imgb0049
     wherein
    R1 denotes methyl or ethyl,
    R2 denotes methyl, ethyl or phenyl, or
    R1 and R2 together form -(CH2)4- ;
    R3 denotes H, n-propyl, -CH2-phenyl or C(=O)-R7;
    R4 denotes H;
    R5 and R6 each denote methyl or together form -(CH2)2-O-(CH2)2-;
    A denotes phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-nitrophenyl or pyridin-3-yl; and
    R7 denotes methyl, phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-methylphenyl,
    excluding
    • benzyl-[2-(dimethylamino-phenyl-methyl)-cyclohexyl]-amine and
    • (2-methyl-1,3-diphenyl-3-piperidin-1-yl-propyl)-propyl-amine.
  2. Compound according to claim 1 or one of its pharmaceutically acceptable salts, wherein the compound of the general structure (I) is present as the diastereomer of the formula (syn,anti-I)
    Figure imgb0050
     and optionally in the enantiomerically pure form.
  3. Compound according to claim 1 or one of its pharmaceutically acceptable salts, wherein the compound of the general structure (I) is present as the diastereomer of the formula (anti,anti-I)
    Figure imgb0051
     and optionally in the enantiomerically pure form.
  4. Compound according to claim 1 or one of its pharmaceutically acceptable salts, wherein the compound of the general structure (I) is present as the diastereomer of the formula (anti,syn-I)
    Figure imgb0052
     and optionally in the enantiomerically pure form.
  5. Compound according to claim 1 or one of its pharmaceutically acceptable salts, wherein the compound of the general structure (I) is present as the diastereomer of the formula (syn,syn-I)
    Figure imgb0053
     and optionally in the enantiomerically pure form.
  6. Compound according to claim 1, or one of its pharmaceutically acceptable salts, which is chosen from:
    1 • (syn,syn)-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]-benzamide or its hydrochloride
    2 • (syn,syn)-2-(dimethylaminopyridin-3-ylmethyl)cyclohexylamine or its hydrochloride
    3 • (syn,syn)-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-fluorobenzamide or its hydrochloride
    4 • (syn,syn)-2-chloro-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]-benzamide or its hydrochloride
    5 • (anti,anti)-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]-benzamide or its hydrochloride
    6 • (anti,anti)-2-(dimethylaminopyridin-3-ylmethyl)cyclohexylamine or its hydrochloride
    7 • (anti,anti)-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-fluorobenzamide or its hydrochloride
    8 • (anti,anti)-2-chloro-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]benzamide or its hydrochloride
    9 • (anti,anti)-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-methylbenzamide or its hydrochloride
    10 • (syn,syn)-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]-2-methylbenzamide or its hydrochloride
    11 • (syn,syn)-N-[2-(dimethylaminopyridin-3-ylmethyl)cyclohexyl]acetamide or its hydrochloride
    12 • (anti, anti) -N- [2- (dimethylaminopyridin-3-ylmethyl)cyclohexyl]acetamide or its hydrochloride
    13 • (syn, syn) -N- [2-(dimethylaminophenylmethyl)cyclohexyl]-2-fluorobenzamide or its hydrochloride
    14 • (syn, syn) -2-(dimethylaminophenylmethyl)cyclohexylamine or its hydrochloride
    15 • (syn,syn)-N-[2-(dimethylamino-phenyl-methyl)-cyclohexyl]-acetamide or its hydrochloride
    16 • (syn,syn)-N-[2-(dimethylamino-phenyl-methyl)-cyclohexyl]-benzamide or its hydrochloride
    17 • (syn,syn)-2-chloro-N-[2-(dimethylamino-phenyl-methyl)-cyclohexyl]-benzamide or its hydrochloride
    18 • (syn,syn)-N-[2-(dimethylamino-phenyl-methyl)-cyclohexyl]-2-methyl-benzamide or its hydrochloride
    19 • (anti, anti) -N- [2- (dimethylamino-phenyl-methyl) - cyclohexyl]-acetamide or its hydrochloride
    20 • (anti,anti)-2-(dimethylamino-phenyl-methyl)-cyclohexylamine or its hydrochloride
    21 • (anti, anti) -N- [2- (dimethylamino-phenyl-methyl)-cyclohexyl]-benzamide or its hydrochloride
    22 • (anti,anti)-N-[2-(dimethylamino-phenyl-methyl)-cyclohexyl]-2-methyl-benzamide or its hydrochloride
    23 • (syn, syn)-2-chloro-N-{2-[(2-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-benzamide or its hydrochloride
    24 • (syn,syn)-2-[(2-chloro-phenyl)-dimethylaminomethyl]-cyclohexylamine or its hydrochloride
    25 • (anti,anti)-2-chloro-N-{2-[(2-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-benzamide or its hydrochloride
    26 • (anti,anti)-2-[(2-chloro-phenyl)-dimethylaminomethyl]-cyclohexylamine or its hydrochloride
    27 • (syn,syn)-N-{2-[(2-chloro-phenyl)-dimethylaminomethyl]-cyclohexyl}-2-fluoro-benzamide or its hydrochloride
    28 • (anti,anti)-N-{2-[dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-benzamide or its hydrochloride
    29 • (anti,anti)-2-[dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexylamine or its hydrochloride
    30 • (anti,anti)-N-{2-[dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-2-fluoro-benzamide or its hydrochloride
    31 • (anti,anti)-2-chloro-N-{2-[dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-benzamide or its hydrochloride
    32 • (anti,anti)-N-{2-[dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-2-methyl-benzamide or its hydrochloride
    33 • (syn, syn) -N-{2- [dimethylamino- (2-nitro-phenyl) - methyl]-cyclohexyl}-acetamide or its hydrochloride
    34 • (syn, syn) -N-2- [dimethylamino- (2-nitro-phenyl) - methyl]-cyclohexylamine or its hydrochloride
    35 • (anti,anti)-N-{2-[(2-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-acetamide or its hydrochloride
    36 • (syn, anti)-2-(dimethylamino-phenyl-methyl)-cyclohexylamine
    37 • (syn,anti)-N-[2-(dimethylamino-phenyl-methyl)-cyclohexyl]-benzamide
    38 • (anti,anti)-N-{2-[dimethylamino-(2-methoxyphenyl)-methyl]-cyclohexyl}-benzamide
    39 • (anti,anti)-N-{2-[dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-benzamide
    40 • (anti,anti)-N-{2-[(2-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-benzamide
    41 • (anti, anti)-N-{2-[dimethylamino-(2-methoxyphenyl)-methyl]-cyclohexyl}-acetamide
    42 • (anti, anti)-2-[dimethylamino-(2-methoxy-phenyl)-methyl]-cyclohexylamine
    43 • (anti,anti)-N-{2-[(2-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-acetamide
    44 • (anti,anti)-2-[(2-chloro-phenyl)-dimethylaminomethyl]-cyclohexylamine
    45 • (anti,anti)-N-{2-[dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexyl}-acetamide
    46 • (anti,anti)-2-[dimethylamino-(2-nitro-phenyl)-methyl]-cyclohexylamine
    47 • (syn,syn)-2-(dimethylamino-phenyl-methyl)-cyclohexylamine
    48 • (syn,syn)-2-[(2-chloro-phenyl)-dimethylaminomethyl]-cyclohexylamine
    49 • (anti,anti)-2-chloro-N-(3-dimethylamino-1-ethyl-2-methyl-3-phenyl-propyl)-benzamide
    50 • (anti,anti)-3-dimethylamino-1-ethyl-2-methyl-3-phenyl-propylamine
    51 • (syn,anti)-2-(dimethylamino-phenyl-methyl)-cyclohexyl-N-(n-propyl)-amine
    52 • (syn,anti)-2-(morpholin-4-yl-phenyl-methyl)-cyclohexyl-N-(n-propyl)-amine
    53 • (syn,anti)-2,N,N-trimethyl-1,3-diphenyl-N'-propyl-propane-1,3-diamine
    54 • (syn, anti)-2-(dimethylamino-phenyl-methyl)-cyclohexyl-N-benzylamine
    55 • (syn,anti)-2-(morpholin-4-yl-phenyl-methyl)-cyclohexyl-N-benzylamine
    56 • (syn, anti)-2,N,N-trimethyl-1,3-diphenyl-N'-benzyl-propane-1,3-diamine
    57 • (syn, anti)-2-(dimethylamino-phenyl-methyl)-cyclohexylamine
    58 • (syn,anti)-2-(morpholin-4-yl-phenyl-methyl)-cyclohexylamine
    59 • (syn,anti)-2,N,N-trimethyl-1,3-diphenyl-propane-1,3-diamine
    60 • (syn,anti)-2-[(2-chlorophenyl)-dimethylaminomethyl]-cyclohexylamine
    63 • (anti,anti)-2-[(2-chlorophenyl)-dimethylaminomethyl]-cyclohexylamine
    62 • (syn,syn)-2-(dimethylamino-phenyl-methyl)-cyclohexylamine
    63 • (anti,anti) -2- (dimethylamino-phenyl-methyl) - cyclohexylamine
    64 • (syn,syn)-2-[(2-chlorophenyl)-dimethylaminomethyl]-cyclohexylamine
    65 • (syn,syn)-2-(dimethylamino-pyridin-3-yl-methyl)-cyclohexylamine
    66 • (anti,anti)-2-(dimethylamino-pyridin-3-yl-methyl)-cyclohexylamine
    67 • (syn,syn)-2-(dimethylamino-(2-methoxyphenyl)-methyl)-cyclohexylamine
    68 • (anti,anti)-2-(dimethylamino-(2-methoxyphenyl)-methyl)-cyclohexylamine
    69 • (syn,syn)-2-(dimethylamino-(2-nitrophenyl)-methyl)-cyclohexylamine
    70 • (anti,anti)-2-(dimethylamino-(2-nitrophenyl)-methyl)-cyclohexylamine.
  7. Process for the preparation of a compound according to claim 1 of the general structure (I) or one of its pharmaceutically acceptable salts
    Figure imgb0054
     wherein
    R1 denotes methyl or ethyl,
    R2 denotes methyl, ethyl or phenyl, or
    R1 and R2 together form - (CH2)4-;
    R3 denotes H, n-propyl or -CH2-phenyl;
    R4 denotes H;
    R5 and R6 each denote methyl or together form -(CH2)2-O-(CH2)2-; and
    A denotes phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-nitrophenyl or pyridin-3-yl,
    characterized in that an imine of the general structure (II)
    Figure imgb0055
     wherein R1, R2, R3, R5, R6 and A are as defined above in this claim,
    is reacted with a suitable reducing agent.
  8. Process according to claim 7, characterized in that the reducing agent is a complex hydride.
  9. Process according to one of claims 7 or 8 for the diastereoselective preparation of a compound of the general structure (anti, anti-I) or one of its pharmaceutically acceptable salts
    Figure imgb0056
     wherein R1, R2, R3, R4, R5, R6 and A are as defined in claim 7,
    characterized in that an imine of the general structure (anti-II)
    Figure imgb0057
     wherein R1, R2, R3, R5, R6 and A are as defined above in this claim,
    is reacted with a suitable reducing agent, in particular zinc cyanoborohydride (ZnCNBH3), LiBH4, NaBH4, NaBH3CN or NaBH(OC(=O)CH3)3, in an alcoholic solvent.
  10. Process according to claim 9, characterized in that the reaction with zinc cyanoborohydride, LiBH4, NaBH4, NaBH3CN or NaBH(OC(=O)CH3)3 is carried out in methanol with warming from 0°C to room temperature over 8 to 24 h, preferably over 10 to 14 h.
  11. Process according to one of claims 7 or 8 for the diastereoselective preparation of a compound of the general structure (syn,syn-I) or one of its pharmaceutically acceptable salts
    Figure imgb0058
     wherein R1, R2, R3, R4, R5, R6 and A are as defined in claim 7,
    characterized in that
    an imine of the general structure (anti-II)
    Figure imgb0059
     wherein R1, R2, R3, R5, R6 and A are as defined above in this claim,
    is reacted with a suitable reducing agent, in particular L-Selectride or diisobutylaluminium hydride, in an ethereal solvent.
  12. Process according to claim 11, characterized in that the reaction is carried out with L-Selectride or diisobutylaluminium hydride in tetrahydrofuran with warming from 0°C to room temperature over 8 to 24 h, preferably over 10 to 14 h.
  13. Process according to one of claims 7 to 12,
    characterized in that the imine of the general structure (II) or (anti-II) is prepared by reaction of the Mannich base (III) or (anti-III)
    Figure imgb0060
     wherein R1, R2, R5, R6 and A are as defined in claim 7, with an amine of the formula R3NH2, if R3 in formula (II) or (anti-II) does not denote H, and with ammonium acetate, if R3 in formula (II) or (anti-II) denotes H, in an ethereal or alcoholic solvent.
  14. Process for the preparation of a compound of the general structure (I) or one of its pharmaceutically acceptable salts
    Figure imgb0061
     wherein
    R1 denotes methyl or ethyl,
    R2 denotes methyl, ethyl or phenyl, or
    R1 and R2 together form - (CH2)4-;
    R3 and R4 denote H;
    R5 and R6 each denote methyl or together form -(CH2)2-O-(CH2)2-; and
    A denotes phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-nitrophenyl or pyridin-3-yl,
    characterized by the process steps:
    (a) conversion of an amino-alcohol of the general structure (IV)
    Figure imgb0062
     wherein R1, R2, R5, R6 and A are as defined above in this claim,
    into the compound of the general structure (V)
    Figure imgb0063
     wherein L denotes mesyl or tosyl;
    (b) conversion of the compound of the general structure (V) into an azide of the general structure (VI)
    Figure imgb0064
     and
    (c) reduction of the azide of the general structure (VI) to the diamine of the general structure (I).
  15. Process according to claim 14 for the diastereoselective preparation of a compound of the general structure (syn,anti-I) or (anti,anti-I) or one of its pharmaceutically acceptable salts
    Figure imgb0065
     wherein R1, R2, R3, R4, R5, R6 and A are as defined in claim 14,
    characterized by the process steps:
    (a') conversion of an amino-alcohol of the general structure (anti,anti-IV) or (syn,anti-IV)
    Figure imgb0066
     wherein R1, R2, R5, R6 and A are as defined above in this claim,
    into the compound of the general structure (anti,anti-V) or (syn, anti-V)
    Figure imgb0067
     wherein L denotes mesyl or tosyl;
    (b') conversion of the compound of the general structure (anti,anti-V) or (syn,anti-V) into an azide of the general structure (syn,anti-VI) or (anti,anti-VI)
    Figure imgb0068
     and
    (c') reduction of the azide of the general structure (syn,anti-VI) or (anti,anti-VI) to the diamine of the general structure (syn,anti-I) or (anti,anti-I).
  16. Process for the preparation of a compound of the general structure (syn,anti-I) or one of its pharmaceutically acceptable salts
    Figure imgb0069
     according to claim 2, wherein
    R1 denotes methyl or ethyl,
    R2 denotes methyl, ethyl or phenyl, or
    R1 and R2 together form -(CH2)4-;
    R3 denotes H, n-propyl or -CH2-phenyl;
    R4 denotes H;
    R5 and R6 each denote methyl or together form -(CH2)2-O-(CH2)2-; and
    A denotes phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-nitrophenyl or pyridin-3-yl,
    characterized by the process steps
    (aa) reaction of an imine of the general structure (VII)
    Figure imgb0070
     wherein R1, R2 and R3 are as defined above in this claim,
    with an iminium salt of the general structure (VIII)
    Figure imgb0071
     wherein R5, R6 and A are as defined above in this claim and Zθ represents a suitable counter-ion;
    and
    (bb) subsequent reduction.
  17. Process according to claim 16 for the preparation of a compound of the general structure (syn,anti-I)
    Figure imgb0072
     wherein R1, R2, R4, R5, R6 and A are as defined in claim 16 and R3 denotes H,
    characterized in that in a further process step (cc) a compound of the general structure (syn,anti-I), wherein R1, R2, R4, R5, R6 and A are as defined in claim 16 and R3 denotes -(CH2)-phenyl, wherein phenyl can be substituted by C1-6-alkyl, is reacted with hydrogen (H2) in the presence of a transition metal which is chosen from platinum, palladium and nickel.
  18. Process for the preparation of a compound of the general structure (I) or one of its pharmaceutically acceptable salts
    Figure imgb0073
     wherein
    R1 denotes methyl or ethyl,
    R2 denotes methyl, ethyl or phenyl, or
    R1 and R2 together form -(CH2)4-;
    R3 denotes C(=O)-R7;
    R4 denotes H;
    R5 and R6 each denote methyl or together form - (CH2)2-O-(CH2)2-;
    A denotes phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-nitrophenyl or pyridin-3-yl; and
    R7 denotes methyl, phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-methylphenyl.
    and which is present as a racemate or in the form of one or more diastereomers or one or more enantiomers,
    characterized in that a compound of the general structure (I) wherein R1, R2, R4, R5, R6 and A are as defined above in this claim and R3 denotes H and which is present as a racemate or in the form of one or more diastereomers or one or more enantiomers is reacted with an acylating reagent.
  19. Process according to claim 18, characterized in that the acylating reagent is an acid chloride of the general formula R7-C(=O)-Cl, wherein R7 denotes methyl, phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-methylphenyl.
  20. Medicaments comprising a compound of the general structure (I) or one of its pharmaceutically acceptable salts, which are/is present as a racemate or in the form of one or more diastereomers or one or more enantiomers
    Figure imgb0074
     wherein
    R1 denotes methyl or ethyl,
    R2 denotes methyl, ethyl or phenyl, or
    R1 and R2 together form -(CH2)4-;
    R3 denotes H, n-propyl , -CH2-phenyl or C(=O)-R7;
    R4 denotes H;
    R5 and R6 each denote methyl or together form -(CH2)2-O-(CH2)2-;
    A denotes phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-nitrophenyl or pyridin-3-yl; and
    R7 denotes methyl, phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-methylphenyl.
  21. Use of a compound of the general structure (I) or one of its pharmaceutically acceptable salts which are/is present as a racemate or in the form of one or more diastereomers or one or more enantiomers,
    Figure imgb0075
     wherein
    R1 denotes methyl or ethyl,
    R2 denotes methyl, ethyl or phenyl, or
    R1 and R2 together form -(CH2)4-;
    R3 denotes H, n-propyl, -CH2-phenyl or C(=O)-R7;
    R4 denotes H;
    R5 and R6 each denote methyl or together form -(CH2)2-O-(CH2)2-;
    A denotes phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-nitrophenyl or pyridin-3-yl; and
    R7 denotes methyl, phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-methylphenyl,
    for the preparation of a medicament for treatment and/or prophylaxis of pain.
  22. Use of a compound of the general structure (I) or one of its pharmaceutically acceptable salts which are/is present as a racemate in the form of one or more diastereomers or one or more enantiomers
    Figure imgb0076
     wherein
    R1 denotes methyl or ethyl,
    R2 denotes methyl, ethyl or phenyl, or
    R1 and R2 together form -(CH2)4-;
    R3 denotes H, n-propyl, -CH2-phenyl or C(=O)-R7;
    R4 denotes H;
    R5 and R6 each denote methyl or together form -(CH2)2-O-(CH2)2-;
    A denotes phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-nitrophenyl or pyridin-3-yl ; and
    R7 denotes methyl, phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-methylphenyl,
    for the preparation of a medicament for treatment and/or prophylaxis of urinary incontinence, itching, tinnitus aurium and/or diarrhoea.
EP02714169A 2001-02-21 2002-02-20 Substituted propane-1,3-diamine derivatives and the pharmaceutical use thereof Expired - Lifetime EP1363885B1 (en)

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